78 FR 47012 - Developing Software Life Cycle Processes Used in Safety Systems of Nuclear Power Plants

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-02

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0195] Developing Software Life Cycle Processes Used in... revised regulatory guide (RG), revision 1 of RG 1.173, ``Developing Software Life Cycle Processes for... Developing a Software Project Life Cycle Process,'' issued 2006, with the clarifications and exceptions as...

Development of Regulatory Documents for Creation (Upgrade) of Physical Protection Systems under the Russian/American MPC&A Program

DOE Office of Scientific and Technical Information (OSTI.GOV)

Izmaylov, Alexandr V.; Babkin, Vladimir; Kurov, Valeriy

2009-10-07

The development of new or the upgrade of existing physical protection systems (PPS) for nuclear facilities involves a multi-step and multidimensional process. The process consists of conceptual design, design, and commissioning stages. The activities associated with each of these stages are governed by Russian government and agency regulations. To ensure a uniform approach to development or upgrading of PPS at Russian nuclear facilities, the development of a range of regulatory and methodological documents is necessary. Some issues of PPS development are covered by the regulatory documents developed by Rosatom, as well as other Russian agencies with nuclear facilities under theirmore » control. This regulatory development has been accomplished as part of the U.S.-Russian MPC&A cooperation or independently by the Russian Federation. While regulatory coverage is extensive, there are a number of issues such as vulnerability analysis, effectiveness assessment, upgrading PPS, and protection of information systems for PPS that require additional regulations be developed. This paper reports on the status of regulatory coverage for PPS development or upgrade, and outlines a new approach to regulatory document development. It describes the evolutionary process of regulatory development through experience gained in the design, development and implementation of PPS as well as experience gained through the cooperative efforts of Russian and U.S. experts involved the development of MPC&A regulations.« less

A transcriptional dynamic network during Arabidopsis thaliana pollen development.

PubMed

Wang, Jigang; Qiu, Xiaojie; Li, Yuhua; Deng, Youping; Shi, Tieliu

2011-01-01

To understand transcriptional regulatory networks (TRNs), especially the coordinated dynamic regulation between transcription factors (TFs) and their corresponding target genes during development, computational approaches would represent significant advances in the genome-wide expression analysis. The major challenges for the experiments include monitoring the time-specific TFs' activities and identifying the dynamic regulatory relationships between TFs and their target genes, both of which are currently not yet available at the large scale. However, various methods have been proposed to computationally estimate those activities and regulations. During the past decade, significant progresses have been made towards understanding pollen development at each development stage under the molecular level, yet the regulatory mechanisms that control the dynamic pollen development processes remain largely unknown. Here, we adopt Networks Component Analysis (NCA) to identify TF activities over time course, and infer their regulatory relationships based on the coexpression of TFs and their target genes during pollen development. We carried out meta-analysis by integrating several sets of gene expression data related to Arabidopsis thaliana pollen development (stages range from UNM, BCP, TCP, HP to 0.5 hr pollen tube and 4 hr pollen tube). We constructed a regulatory network, including 19 TFs, 101 target genes and 319 regulatory interactions. The computationally estimated TF activities were well correlated to their coordinated genes' expressions during the development process. We clustered the expression of their target genes in the context of regulatory influences, and inferred new regulatory relationships between those TFs and their target genes, such as transcription factor WRKY34, which was identified that specifically expressed in pollen, and regulated several new target genes. Our finding facilitates the interpretation of the expression patterns with more biological relevancy, since the clusters corresponding to the activity of specific TF or the combination of TFs suggest the coordinated regulation of TFs to their target genes. Through integrating different resources, we constructed a dynamic regulatory network of Arabidopsis thaliana during pollen development with gene coexpression and NCA. The network illustrated the relationships between the TFs' activities and their target genes' expression, as well as the interactions between TFs, which provide new insight into the molecular mechanisms that control the pollen development.

Information Quality in Regulatory Decision Making: Peer Review versus Good Laboratory Practice.

PubMed

McCarty, Lynn S; Borgert, Christopher J; Mihaich, Ellen M

2012-07-01

There is an ongoing discussion on the provenance of toxicity testing data regarding how best to ensure its validity and credibility. A central argument is whether journal peer-review procedures are superior to Good Laboratory Practice (GLP) standards employed for compliance with regulatory mandates. We sought to evaluate the rationale for regulatory decision making based on peer-review procedures versus GLP standards. We examined pertinent published literature regarding how scientific data quality and validity are evaluated for peer review, GLP compliance, and development of regulations. Some contend that peer review is a coherent, consistent evaluative procedure providing quality control for experimental data generation, analysis, and reporting sufficient to reliably establish relative merit, whereas GLP is seen as merely a tracking process designed to thwart investigator corruption. This view is not supported by published analyses pointing to subjectivity and variability in peer-review processes. Although GLP is not designed to establish relative merit, it is an internationally accepted quality assurance, quality control method for documenting experimental conduct and data. Neither process is completely sufficient for establishing relative scientific soundness. However, changes occurring both in peer-review processes and in regulatory guidance resulting in clearer, more transparent communication of scientific information point to an emerging convergence in ensuring information quality. The solution to determining relative merit lies in developing a well-documented, generally accepted weight-of-evidence scheme to evaluate both peer-reviewed and GLP information used in regulatory decision making where both merit and specific relevance inform the process.

Proteomics for Adverse Outcome Pathway Discovery using Human Kidney Cells?

EPA Science Inventory

An Adverse Outcome Pathway (AOP) is a conceptual framework that applies molecular-based data for use in risk assessment and regulatory decision support. AOP development is based on effects data of chemicals on biological processes (i.e., molecular initiating events, key intermedi...

Boolean Dynamic Modeling Approaches to Study Plant Gene Regulatory Networks: Integration, Validation, and Prediction.

PubMed

Velderraín, José Dávila; Martínez-García, Juan Carlos; Álvarez-Buylla, Elena R

2017-01-01

Mathematical models based on dynamical systems theory are well-suited tools for the integration of available molecular experimental data into coherent frameworks in order to propose hypotheses about the cooperative regulatory mechanisms driving developmental processes. Computational analysis of the proposed models using well-established methods enables testing the hypotheses by contrasting predictions with observations. Within such framework, Boolean gene regulatory network dynamical models have been extensively used in modeling plant development. Boolean models are simple and intuitively appealing, ideal tools for collaborative efforts between theorists and experimentalists. In this chapter we present protocols used in our group for the study of diverse plant developmental processes. We focus on conceptual clarity and practical implementation, providing directions to the corresponding technical literature.

Development of the risk-based, phased-in approach for the international harmonization of the regulation of container closure systems for drugs in Taiwan.

PubMed

Chang, Lin-Chau; Kang, Jaw-Jou; Gau, Churn-Shiouh

2016-06-01

The main concern for container closure systems of drugs is to ensure suitability for the intended use which is associated with issues regarding protection, compatibility, safety, and performance. Among various concerns, leachables may pose a safety hazard to patients, while risks might vary depending on the dosage form and the administration route. Stringent regulatory authorities such as the European Medicines Agency and the United States Food and Drug Administration have established risk-based regulatory requirements and published corresponding guidelines to facilitate implementation. Taiwan, a member of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme, makes every effort to harmonize with international regulations and to strengthen protection of public health through regulatory controls. The aim of the present study was to investigate the regulatory framework and policies set by stringent regulatory authorities. The strategy proposed for the development of an eventual guideline was sent to the Taiwan Food and Drug Administration for decision. A risk-based, phased-in approach which was extensively discussed in the expert committee was proposed. The approach proposed herein could also serve as a starting point which is worth considered by other countries in which international harmonization is in process. Copyright © 2016 Elsevier Inc. All rights reserved.

Scientific and Regulatory Considerations for Generic Complex Drug Products Containing Nanomaterials.

PubMed

Zheng, Nan; Sun, Dajun D; Zou, Peng; Jiang, Wenlei

2017-05-01

In the past few decades, the development of medicine at the nanoscale has been applied to oral and parenteral dosage forms in a wide range of therapeutic areas to enhance drug delivery and reduce toxicity. An obvious response to these benefits is reflected in higher market shares of complex drug products containing nanomaterials than that of conventional formulations containing the same active ingredient. The surging market interest has encouraged the pharmaceutical industry to develop cost-effective generic versions of complex drug products based on nanotechnology when the associated patent and exclusivity on the reference products have expired. Due to their complex nature, nanotechnology-based drugs present unique challenges in determining equivalence standards between generic and innovator products. This manuscript attempts to provide the scientific rationales and regulatory considerations of key equivalence standards (e.g., in vivo studies and in vitro physicochemical characterization) for oral drugs containing nanomaterials, iron-carbohydrate complexes, liposomes, protein-bound drugs, nanotube-forming drugs, and nano emulsions. It also presents active research studies in bridging regulatory and scientific gaps for establishing equivalence of complex products containing nanomaterials. We hope that open communication among industry, academia, and regulatory agencies will accelerate the development and approval processes of generic complex products based on nanotechnology.

RNAi technologies in agricultural biotechnology: The Toxicology Forum 40th Annual Summer Meeting.

PubMed

Sherman, James H; Munyikwa, Tichafa; Chan, Stephen Y; Petrick, Jay S; Witwer, Kenneth W; Choudhuri, Supratim

2015-11-01

During the 40th Annual Meeting of The Toxicology Forum, the current and potential future science, regulations, and politics of agricultural biotechnology were presented and discussed. The meeting session described herein focused on the technology of RNA interference (RNAi) in agriculture. The general process by which RNAi works, currently registered RNAi-based plant traits, example RNAi-based traits in development, potential use of double stranded RNA (dsRNA) as topically applied pesticide active ingredients, research related to the safety of RNAi, biological barriers to ingested dsRNA, recent regulatory RNAi science reviews, and regulatory considerations related to the use of RNAi in agriculture were discussed. Participants generally agreed that the current regulatory framework is robust and appropriate for evaluating the safety of RNAi employed in agricultural biotechnology and were also supportive of the use of RNAi to develop improved crop traits. However, as with any emerging technology, the potential range of future products, potential future regulatory frameworks, and public acceptance of the technology will continue to evolve. As such, continuing dialogue was encouraged to promote education of consumers and science-based regulations. Copyright © 2015 Elsevier Inc. All rights reserved.

Pharmacogenetics and pharmacogenomics in drug development and regulatory decision making: report of the first FDA-PWG-PhRMA-DruSafe Workshop.

PubMed

Lesko, Lawrence J; Salerno, Ronald A; Spear, Brian B; Anderson, Donald C; Anderson, Timothy; Brazell, Celia; Collins, Jerry; Dorner, Andrew; Essayan, David; Gomez-Mancilla, Baltazar; Hackett, Joseph; Huang, Shiew-Mei; Ide, Susan; Killinger, Joanne; Leighton, John; Mansfield, Elizabeth; Meyer, Robert; Ryan, Stephen G; Schmith, Virginia; Shaw, Peter; Sistare, Frank; Watson, Mark; Worobec, Alexandra

2003-04-01

The use of pharmacogenetics and pharmacogenomics in the drug development process, and in the assessment of such data submitted to regulatory agencies by industry, has generated significant enthusiasm as well as important reservations within the scientific and medical communities. This situation has arisen because of the increasing number of exploratory and confirmatory investigations into variations in RNA expression patterns and DNA sequences being conducted in the preclinical and clinical phases of drug development, and the uncertainty surrounding the acceptance of these data by regulatory agencies. This report summarizes the outcome of a workshop cosponsored by the Food and Drug Administration (FDA), the Pharmacogenetics Working Group (PWG), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the PhRMA Preclinical Safety Committee (DruSafe). The specific aim of the workshop was to identify key issues associated with the application of pharmacogenetics and pharmacogenomics, including the feasibility of a regulatory "safe harbor" for exploratory genome-based data, and to provide a forum for industry-regulatory agency dialogue on these important issues.

Uncovering transcription factor and microRNA risk regulatory pathways associated with osteoarthritis by network analysis.

PubMed

Song, Zhenhua; Zhang, Chi; He, Lingxiao; Sui, Yanfang; Lin, Xiafei; Pan, Jingjing

2018-06-12

Osteoarthritis (OA) is the most common form of joint disease. The development of inflammation have been considered to play a key role during the progression of OA. Regulatory pathways are known to play crucial roles in many pathogenic processes. Thus, deciphering these risk regulatory pathways is critical for elucidating the mechanisms underlying OA. We constructed an OA-specific regulatory network by integrating comprehensive curated transcription and post-transcriptional resource involving transcription factor (TF) and microRNA (miRNA). To deepen our understanding of underlying molecular mechanisms of OA, we developed an integrated systems approach to identify OA-specific risk regulatory pathways. In this study, we identified 89 significantly differentially expressed genes between normal and inflamed areas of OA patients. We found the OA-specific regulatory network was a standard scale-free network with small-world properties. It significant enriched many immune response-related functions including leukocyte differentiation, myeloid differentiation and T cell activation. Finally, 141 risk regulatory pathways were identified based on OA-specific regulatory network, which contains some known regulator of OA. The risk regulatory pathways may provide clues for the etiology of OA and be a potential resource for the discovery of novel OA-associated disease genes. Copyright © 2018 Elsevier Inc. All rights reserved.

MIR@NT@N: a framework integrating transcription factors, microRNAs and their targets to identify sub-network motifs in a meta-regulation network model

PubMed Central

2011-01-01

Background To understand biological processes and diseases, it is crucial to unravel the concerted interplay of transcription factors (TFs), microRNAs (miRNAs) and their targets within regulatory networks and fundamental sub-networks. An integrative computational resource generating a comprehensive view of these regulatory molecular interactions at a genome-wide scale would be of great interest to biologists, but is not available to date. Results To identify and analyze molecular interaction networks, we developed MIR@NT@N, an integrative approach based on a meta-regulation network model and a large-scale database. MIR@NT@N uses a graph-based approach to predict novel molecular actors across multiple regulatory processes (i.e. TFs acting on protein-coding or miRNA genes, or miRNAs acting on messenger RNAs). Exploiting these predictions, the user can generate networks and further analyze them to identify sub-networks, including motifs such as feedback and feedforward loops (FBL and FFL). In addition, networks can be built from lists of molecular actors with an a priori role in a given biological process to predict novel and unanticipated interactions. Analyses can be contextualized and filtered by integrating additional information such as microarray expression data. All results, including generated graphs, can be visualized, saved and exported into various formats. MIR@NT@N performances have been evaluated using published data and then applied to the regulatory program underlying epithelium to mesenchyme transition (EMT), an evolutionary-conserved process which is implicated in embryonic development and disease. Conclusions MIR@NT@N is an effective computational approach to identify novel molecular regulations and to predict gene regulatory networks and sub-networks including conserved motifs within a given biological context. Taking advantage of the M@IA environment, MIR@NT@N is a user-friendly web resource freely available at http://mironton.uni.lu which will be updated on a regular basis. PMID:21375730

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tweedie, A.; Doris, E.

Establishing interconnection to the grid is a recognized barrier to the deployment of distributed energy generation. This report compares interconnection processes for photovoltaic projects in California and Germany. This report summarizes the steps of the interconnection process for developers and utilities, the average length of time utilities take to process applications, and paperwork required of project developers. Based on a review of the available literature, this report finds that while the interconnection procedures and timelines are similar in California and Germany, differences in the legal and regulatory frameworks are substantial.

College of American Pathologists' laboratory standards for next-generation sequencing clinical tests.

PubMed

Aziz, Nazneen; Zhao, Qin; Bry, Lynn; Driscoll, Denise K; Funke, Birgit; Gibson, Jane S; Grody, Wayne W; Hegde, Madhuri R; Hoeltge, Gerald A; Leonard, Debra G B; Merker, Jason D; Nagarajan, Rakesh; Palicki, Linda A; Robetorye, Ryan S; Schrijver, Iris; Weck, Karen E; Voelkerding, Karl V

2015-04-01

The higher throughput and lower per-base cost of next-generation sequencing (NGS) as compared to Sanger sequencing has led to its rapid adoption in clinical testing. The number of laboratories offering NGS-based tests has also grown considerably in the past few years, despite the fact that specific Clinical Laboratory Improvement Amendments of 1988/College of American Pathologists (CAP) laboratory standards had not yet been developed to regulate this technology. To develop a checklist for clinical testing using NGS technology that sets standards for the analytic wet bench process and for bioinformatics or "dry bench" analyses. As NGS-based clinical tests are new to diagnostic testing and are of much greater complexity than traditional Sanger sequencing-based tests, there is an urgent need to develop new regulatory standards for laboratories offering these tests. To develop the necessary regulatory framework for NGS and to facilitate appropriate adoption of this technology for clinical testing, CAP formed a committee in 2011, the NGS Work Group, to deliberate upon the contents to be included in the checklist. Results . -A total of 18 laboratory accreditation checklist requirements for the analytic wet bench process and bioinformatics analysis processes have been included within CAP's molecular pathology checklist (MOL). This report describes the important issues considered by the CAP committee during the development of the new checklist requirements, which address documentation, validation, quality assurance, confirmatory testing, exception logs, monitoring of upgrades, variant interpretation and reporting, incidental findings, data storage, version traceability, and data transfer confidentiality.

Modularity and design principles in the sea urchin embryo gene regulatory network

PubMed Central

Peter, Isabelle S.; Davidson, Eric H.

2010-01-01

The gene regulatory network (GRN) established experimentally for the pre-gastrular sea urchin embryo provides causal explanations of the biological functions required for spatial specification of embryonic regulatory states. Here we focus on the structure of the GRN which controls the progressive increase in complexity of territorial regulatory states during embryogenesis; and on the types of modular subcircuits of which the GRN is composed. Each of these subcircuit topologies executes a particular operation of spatial information processing. The GRN architecture reflects the particular mode of embryogenesis represented by sea urchin development. Network structure not only specifies the linkages constituting the genomic regulatory code for development, but also indicates the various regulatory requirements of regional developmental processes. PMID:19932099

Use of new scientific developments in regulatory risk assessments: challenges and opportunities.

PubMed

Tarazona, Jose V

2013-07-01

Since the 1990s, science based ecological risk assessments constitute an essential tool for supporting decision making in the regulatory context. Using the European REACH Regulation as example, this article presents the challenges and opportunities for new scientific developments within the area of chemical control and environmental protection. These challenges can be sorted out in 3 main related topics (sets). In the short term, the challenges are directly associated with the regulatory requirements, required for facilitating a scientifically sound implementation of the different obligations for industry and authorities. It is important to mention that although the actual tools are different due to the regulatory requirements, the basic needs are still the same as those addressed in the early 1990s: understanding the ecological relevance of the predicted effects, including the uncertainty, and facilitating the link with the socio-economic assessment. The second set of challenges covers the opportunities for getting an added value from the regulatory efforts. The information compiled through REACH registration and notification processes is analyzed as source for new integrative developments for assessing the combined chemical risk at the regional level. Finally, the article discusses the challenge of inverting the process and developing risk assessment methods focusing on the receptor, the individual or ecosystem, instead of on the stressor or source. These approaches were limited in the past due to the lack of information, but the identification and dissemination of standard information, including uses, manufacturing sites, physical-chemical, environmental, ecotoxicological, and toxicological properties as well as operational conditions and risk management measures for thousands of chemicals, combined by the knowledge gathered through large scale monitoring programs and spatial information systems is generating new opportunities. The challenge is liking predictions and measured data in an integral "-omic type" approach, considering collectively data from different sources and offering a complete assessment of the chemical risk of individuals and ecosystems, with new conceptual approaches that could be defined as "risk-omics based" paradigms and models. Copyright © 2013 SETAC.

Genomics in the land of regulatory science.

PubMed

Tong, Weida; Ostroff, Stephen; Blais, Burton; Silva, Primal; Dubuc, Martine; Healy, Marion; Slikker, William

2015-06-01

Genomics science has played a major role in the generation of new knowledge in the basic research arena, and currently question arises as to its potential to support regulatory processes. However, the integration of genomics in the regulatory decision-making process requires rigorous assessment and would benefit from consensus amongst international partners and research communities. To that end, the Global Coalition for Regulatory Science Research (GCRSR) hosted the fourth Global Summit on Regulatory Science (GSRS2014) to discuss the role of genomics in regulatory decision making, with a specific emphasis on applications in food safety and medical product development. Challenges and issues were discussed in the context of developing an international consensus for objective criteria in the analysis, interpretation and reporting of genomics data with an emphasis on transparency, traceability and "fitness for purpose" for the intended application. It was recognized that there is a need for a global path in the establishment of a regulatory bioinformatics framework for the development of transparent, reliable, reproducible and auditable processes in the management of food and medical product safety risks. It was also recognized that training is an important mechanism in achieving internationally consistent outcomes. GSRS2014 provided an effective venue for regulators andresearchers to meet, discuss common issues, and develop collaborations to address the challenges posed by the application of genomics to regulatory science, with the ultimate goal of wisely integrating novel technical innovations into regulatory decision-making. Published by Elsevier Inc.

Industrial Adoption of Model-Based Systems Engineering: Challenges and Strategies

NASA Astrophysics Data System (ADS)

Maheshwari, Apoorv

As design teams are becoming more globally integrated, one of the biggest challenges is to efficiently communicate across the team. The increasing complexity and multi-disciplinary nature of the products are also making it difficult to keep track of all the information generated during the design process by these global team members. System engineers have identified Model-based Systems Engineering (MBSE) as a possible solution where the emphasis is placed on the application of visual modeling methods and best practices to systems engineering (SE) activities right from the beginning of the conceptual design phases through to the end of the product lifecycle. Despite several advantages, there are multiple challenges restricting the adoption of MBSE by industry. We mainly consider the following two challenges: a) Industry perceives MBSE just as a diagramming tool and does not see too much value in MBSE; b) Industrial adopters are skeptical if the products developed using MBSE approach will be accepted by the regulatory bodies. To provide counter evidence to the former challenge, we developed a generic framework for translation from an MBSE tool (Systems Modeling Language, SysML) to an analysis tool (Agent-Based Modeling, ABM). The translation is demonstrated using a simplified air traffic management problem and provides an example of a potential quite significant value: the ability to use MBSE representations directly in an analysis setting. For the latter challenge, we are developing a reference model that uses SysML to represent a generic infusion pump and SE process for planning, developing, and obtaining regulatory approval of a medical device. This reference model demonstrates how regulatory requirements can be captured effectively through model-based representations. We will present another case study at the end where we will apply the knowledge gained from both case studies to a UAV design problem.

Control Systems Engineering in Continuous Pharmaceutical Manufacturing May 20-21, 2014 Continuous Manufacturing Symposium.

PubMed

Myerson, Allan S; Krumme, Markus; Nasr, Moheb; Thomas, Hayden; Braatz, Richard D

2015-03-01

This white paper provides a perspective of the challenges, research needs, and future directions for control systems engineering in continuous pharmaceutical processing. The main motivation for writing this paper is to facilitate the development and deployment of control systems technologies so as to ensure quality of the drug product. Although the main focus is on small-molecule pharmaceutical products, most of the same statements apply to biological drug products. An introduction to continuous manufacturing and control systems is followed by a discussion of the current status and technical needs in process monitoring and control, systems integration, and risk analysis. Some key points are that: (1) the desired objective in continuous manufacturing should be the satisfaction of all critical quality attributes (CQAs), not for all variables to operate at steady-state values; (2) the design of start-up and shutdown procedures can significantly affect the economic operation of a continuous manufacturing process; (3) the traceability of material as it moves through the manufacturing facility is an important consideration that can at least in part be addressed using residence time distributions; and (4) the control systems technologies must assure quality in the presence of disturbances, dynamics, uncertainties, nonlinearities, and constraints. Direct measurement, first-principles and empirical model-based predictions, and design space approaches are described for ensuring that CQA specifications are met. Ways are discussed for universities, regulatory bodies, and industry to facilitate working around or through barriers to the development of control systems engineering technologies for continuous drug manufacturing. Industry and regulatory bodies should work with federal agencies to create federal funding mechanisms to attract faculty to this area. Universities should hire faculty interested in developing first-principles models and control systems technologies for drug manufacturing that are easily transportable to industry. Industry can facilitate the move to continuous manufacturing by working with universities on the conception of new continuous pharmaceutical manufacturing process unit operations that have the potential to make major improvements in product quality, controllability, or reduced capital and/or operating costs. Regulatory bodies should ensure that: (1) regulations and regulatory practices promote, and do not derail, the development and implementation of continuous manufacturing and control systems engineering approaches; (2) the individuals who approve specific regulatory filings are sufficiently trained to make good decisions regarding control systems approaches; (3) provide regulatory clarity and eliminate/reduce regulatory risks; (4) financially support the development of high-quality training materials for use of undergraduate students, graduate students, industrial employees, and regulatory staff; (5) enhance the training of their own technical staff by financially supporting joint research projects with universities in the development of continuous pharmaceutical manufacturing processes and the associated control systems engineering theory, numerical algorithms, and software; and (6) strongly encourage the federal agencies that support research to fund these research areas. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Control systems engineering in continuous pharmaceutical manufacturing. May 20-21, 2014 Continuous Manufacturing Symposium.

PubMed

Myerson, Allan S; Krumme, Markus; Nasr, Moheb; Thomas, Hayden; Braatz, Richard D

2015-03-01

This white paper provides a perspective of the challenges, research needs, and future directions for control systems engineering in continuous pharmaceutical processing. The main motivation for writing this paper is to facilitate the development and deployment of control systems technologies so as to ensure quality of the drug product. Although the main focus is on small-molecule pharmaceutical products, most of the same statements apply to biological drug products. An introduction to continuous manufacturing and control systems is followed by a discussion of the current status and technical needs in process monitoring and control, systems integration, and risk analysis. Some key points are that: (1) the desired objective in continuous manufacturing should be the satisfaction of all critical quality attributes (CQAs), not for all variables to operate at steady-state values; (2) the design of start-up and shutdown procedures can significantly affect the economic operation of a continuous manufacturing process; (3) the traceability of material as it moves through the manufacturing facility is an important consideration that can at least in part be addressed using residence time distributions; and (4) the control systems technologies must assure quality in the presence of disturbances, dynamics, uncertainties, nonlinearities, and constraints. Direct measurement, first-principles and empirical model-based predictions, and design space approaches are described for ensuring that CQA specifications are met. Ways are discussed for universities, regulatory bodies, and industry to facilitate working around or through barriers to the development of control systems engineering technologies for continuous drug manufacturing. Industry and regulatory bodies should work with federal agencies to create federal funding mechanisms to attract faculty to this area. Universities should hire faculty interested in developing first-principles models and control systems technologies for drug manufacturing that are easily transportable to industry. Industry can facilitate the move to continuous manufacturing by working with universities on the conception of new continuous pharmaceutical manufacturing process unit operations that have the potential to make major improvements in product quality, controllability, or reduced capital and/or operating costs. Regulatory bodies should ensure that: (1) regulations and regulatory practices promote, and do not derail, the development and implementation of continuous manufacturing and control systems engineering approaches; (2) the individuals who approve specific regulatory filings are sufficiently trained to make good decisions regarding control systems approaches; (3) provide regulatory clarity and eliminate/reduce regulatory risks; (4) financially support the development of high-quality training materials for use of undergraduate students, graduate students, industrial employees, and regulatory staff; (5) enhance the training of their own technical staff by financially supporting joint research projects with universities in the development of continuous pharmaceutical manufacturing processes and the associated control systems engineering theory, numerical algorithms, and software; and (6) strongly encourage the federal agencies that support research to fund these research areas. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Challenges for modeling global gene regulatory networks during development: insights from Drosophila.

PubMed

Wilczynski, Bartek; Furlong, Eileen E M

2010-04-15

Development is regulated by dynamic patterns of gene expression, which are orchestrated through the action of complex gene regulatory networks (GRNs). Substantial progress has been made in modeling transcriptional regulation in recent years, including qualitative "coarse-grain" models operating at the gene level to very "fine-grain" quantitative models operating at the biophysical "transcription factor-DNA level". Recent advances in genome-wide studies have revealed an enormous increase in the size and complexity or GRNs. Even relatively simple developmental processes can involve hundreds of regulatory molecules, with extensive interconnectivity and cooperative regulation. This leads to an explosion in the number of regulatory functions, effectively impeding Boolean-based qualitative modeling approaches. At the same time, the lack of information on the biophysical properties for the majority of transcription factors within a global network restricts quantitative approaches. In this review, we explore the current challenges in moving from modeling medium scale well-characterized networks to more poorly characterized global networks. We suggest to integrate coarse- and find-grain approaches to model gene regulatory networks in cis. We focus on two very well-studied examples from Drosophila, which likely represent typical developmental regulatory modules across metazoans. Copyright (c) 2009 Elsevier Inc. All rights reserved.

Training Materials Developed for Latino Entrepreneurs

ERIC Educational Resources Information Center

Abreo, Christina; Miller, Wayne; Farmer, Frank; Moon, Zola; McCullough, Stacey

2014-01-01

This article describes the materials and training program that Extension created to assist current and potential Latino immigrant entrepreneurs in starting businesses in Arkansas. The content-based educational materials describe the process for starting a new business, government regulatory requirements, start-up costs and considerations, and how…

Establishing a Quality Control System for Stem Cell-Based Medicinal Products in China

PubMed Central

2015-01-01

Stem cell-based medicinal products (SCMPs) are emerging as novel therapeutic products. The success of its development depends on the existence of an effective quality control system, which is constituted by quality control technologies, standards, reference materials, guidelines, and the associated management system in accordance with regulatory requirements along product lifespan. However, a worldwide, effective quality control system specific for SCMPs is still far from established partially due to the limited understanding of stem cell sciences and lack of quality control technologies for accurately assessing the safety and biological effectiveness of SCMPs before clinical use. Even though, based on the existing regulations and current stem cell sciences and technologies, initial actions toward the goal of establishing such a system have been taken as exemplified by recent development of new “interim guidelines” for governing quality control along development of SCMPs and new development of the associated quality control technologies in China. In this review, we first briefly introduced the major institutions involved in the regulation of cell substrates and therapeutic cell products in China and the existing regulatory documents and technical guidelines used as critical references for developing the new interim guidelines. With focus only on nonhematopoietic stem cells, we then discussed the principal quality attributes of SCMPs as well as our thinking of proper testing approaches to be established with relevant evaluation technologies to ensure all quality requirements of SCMPs along different manufacturing processes and development stages. At the end, some regulatory and technical challenges were also discussed with the conclusion that combined efforts should be taken to promote stem cell regulatory sciences to establish the effective quality control system for SCMPs. PMID:25471126

Hydropower Regulatory and Permitting Information Desktop (RAPID) Toolkit

DOE Office of Scientific and Technical Information (OSTI.GOV)

Levine, Aaron L

Hydropower Regulatory and Permitting Information Desktop (RAPID) Toolkit presentation from the WPTO FY14-FY16 Peer Review. The toolkit is aimed at regulatory agencies, consultants, project developers, the public, and any other party interested in learning more about the hydropower regulatory process.

Challenges in orphan drug development and regulatory policy in China.

PubMed

Cheng, Alice; Xie, Zhi

2017-01-18

While regulatory policy is well defined for orphan drug development in the United States and Europe, rare disease policy in China is still evolving. Many Chinese patients currently pay out of pocket for international treatments that are not yet approved in China. The lack of a clear definition and therefore regulatory approval process for rare diseases has, until now, de-incentivized pharmaceutical companies to pursue rare disease drug development in China. In turn, many grassroots movements have begun to support rare disease patients and facilitate drug discovery through research. Recently, the Chinese FDA set new regulatory guidelines for drugs being developed in China, including an expedited review process for life-saving treatments. In this review, we discuss the effects of these new policy changes on and suggest potential solutions to innovate orphan drug development in China.

Plant MetGenMAP: an integrative analysis system for plant systems biology

USDA-ARS?s Scientific Manuscript database

We have developed a web-based system, Plant MetGenMAP, which can identify significantly altered biochemical pathways and highly affected biological processes, predict functional roles of pathway genes, and potential pathway-related regulatory motifs from transcript and metabolite profile datasets. P...

Small RNA-mediated regulation in bacteria: A growing palette of diverse mechanisms.

PubMed

Dutta, Tanmay; Srivastava, Shubhangi

2018-05-20

Small RNAs (sRNAs) in bacteria have evolved with diverse mechanisms to balance their target gene expression in response to changes in the environment. Accumulating studies on bacterial regulatory processes firmly established that sRNAs modulate their target gene expression generally at the posttranscriptional level. Identification of large number of sRNAs by advanced technologies, like deep sequencing, tilling microarray, indicates the existence of a plethora of distinctive sRNA-mediated regulatory mechanisms in bacteria. Types of the novel mechanisms are increasing with the discovery of new sRNAs. Complementary base pairing between sRNAs and target RNAs assisted by RNA chaperones like Hfq and ProQ, in many occasions, to regulate the cognate gene expression is prevalent in sRNA mechanisms. sRNAs, in most studied cases, can directly base pair with target mRNA to remodel its expression. Base pairing can happen either in the untranslated regions or in the coding regions of mRNA to activate/repress its translation. sRNAs also act as target mimic to titrate away different regulatory RNAs from its target. Other mechanism includes the sequestration of regulatory proteins, especially transcription factors, by sRNAs. Numerous sRNAs, following analogous mechanism, are widespread in bacteria, and thus, has drawn immense attention for the development of RNA-based technologies. Nevertheless, typical sRNA mechanisms are also discovered to be confined in some bacteria. Analysis of the sRNA mechanisms unravels their existence in both the single step processes and the complex regulatory networks with a global effect on cell physiology. This review deals with the diverse array of mechanisms, which sRNAs follow to maintain bacterial lifestyle. Copyright © 2018 Elsevier B.V. All rights reserved.

Regulatory Technology Development Plan - Sodium Fast Reactor. Mechanistic Source Term - Trial Calculation. Work Plan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grabaskas, David; Bucknor, Matthew; Jerden, James

2016-02-01

The overall objective of the SFR Regulatory Technology Development Plan (RTDP) effort is to identify and address potential impediments to the SFR regulatory licensing process. In FY14, an analysis by Argonne identified the development of an SFR-specific MST methodology as an existing licensing gap with high regulatory importance and a potentially long lead-time to closure. This work was followed by an initial examination of the current state-of-knowledge regarding SFR source term development (ANLART-3), which reported several potential gaps. Among these were the potential inadequacies of current computational tools to properly model and assess the transport and retention of radionuclides duringmore » a metal fuel pool-type SFR core damage incident. The objective of the current work is to determine the adequacy of existing computational tools, and the associated knowledge database, for the calculation of an SFR MST. To accomplish this task, a trial MST calculation will be performed using available computational tools to establish their limitations with regard to relevant radionuclide release/retention/transport phenomena. The application of existing modeling tools will provide a definitive test to assess their suitability for an SFR MST calculation, while also identifying potential gaps in the current knowledge base and providing insight into open issues regarding regulatory criteria/requirements. The findings of this analysis will assist in determining future research and development needs.« less

75 FR 6422 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-09

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving Proposed Rule Change... Incorporated NYSE Rule 411(a)(ii)(5) as Part of the Process of Developing the Consolidated FINRA Rulebook February 2, 2010. On December 4, 2009, the Financial Industry Regulatory Authority, Inc. (``FINRA'') (f/k/a...

Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies-the German Cancer Consortium approach.

PubMed

Krackhardt, Angela M; Anliker, Brigitte; Hildebrandt, Martin; Bachmann, Michael; Eichmüller, Stefan B; Nettelbeck, Dirk M; Renner, Matthias; Uharek, Lutz; Willimsky, Gerald; Schmitt, Michael; Wels, Winfried S; Schüssler-Lenz, Martina

2018-04-01

Adoptive transfer of T cells genetically modified by TCRs or CARs represents a highly attractive novel therapeutic strategy to treat malignant diseases. Various approaches for the development of such gene therapy medicinal products (GTMPs) have been initiated by scientists in recent years. To date, however, the number of clinical trials commenced in Germany and Europe is still low. Several hurdles may contribute to the delay in clinical translation of these therapeutic innovations including the significant complexity of manufacture and non-clinical testing of these novel medicinal products, the limited knowledge about the intricate regulatory requirements of the academic developers as well as limitations of funds for clinical testing. A suitable good manufacturing practice (GMP) environment is a key prerequisite and platform for the development, validation, and manufacture of such cell-based therapies, but may also represent a bottleneck for clinical translation. The German Cancer Consortium (DKTK) and the Paul-Ehrlich-Institut (PEI) have initiated joint efforts of researchers and regulators to facilitate and advance early phase, academia-driven clinical trials. Starting with a workshop held in 2016, stakeholders from academia and regulatory authorities in Germany have entered into continuing discussions on a diversity of scientific, manufacturing, and regulatory aspects, as well as the benefits and risks of clinical application of CAR/TCR-based cell therapies. This review summarizes the current state of discussions of this cooperative approach providing a basis for further policy-making and suitable modification of processes.

Predictive computation of genomic logic processing functions in embryonic development

PubMed Central

Peter, Isabelle S.; Faure, Emmanuel; Davidson, Eric H.

2012-01-01

Gene regulatory networks (GRNs) control the dynamic spatial patterns of regulatory gene expression in development. Thus, in principle, GRN models may provide system-level, causal explanations of developmental process. To test this assertion, we have transformed a relatively well-established GRN model into a predictive, dynamic Boolean computational model. This Boolean model computes spatial and temporal gene expression according to the regulatory logic and gene interactions specified in a GRN model for embryonic development in the sea urchin. Additional information input into the model included the progressive embryonic geometry and gene expression kinetics. The resulting model predicted gene expression patterns for a large number of individual regulatory genes each hour up to gastrulation (30 h) in four different spatial domains of the embryo. Direct comparison with experimental observations showed that the model predictively computed these patterns with remarkable spatial and temporal accuracy. In addition, we used this model to carry out in silico perturbations of regulatory functions and of embryonic spatial organization. The model computationally reproduced the altered developmental functions observed experimentally. Two major conclusions are that the starting GRN model contains sufficiently complete regulatory information to permit explanation of a complex developmental process of gene expression solely in terms of genomic regulatory code, and that the Boolean model provides a tool with which to test in silico regulatory circuitry and developmental perturbations. PMID:22927416

75 FR 61502 - Cooperative Agreement With the Pan American Health Organization for the Development of an...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-05

... Medical Products and Related Regulatory Processes and Systems in the Americas Region AGENCY: Food and Drug... Health Organization (PAHO) for the development of an information hub in the areas of medical products and related regulatory processes and systems (e.g., including drugs, biologics, vaccines, medical devices, and...

Connecting pre-marketing clinical research and medical practice: opinion-based study of core issues and possible changes in drug regulation.

PubMed

Wieringa, Nicolien F; Peschar, Jules L; Denig, Petra; de Graeff, Pieter A; Vos, Rein

2003-01-01

To identify core issues that contribute to the gap between pre-marketing clinical research and practice as seen from the perspective of medical practice, as well as possible changes and potential barriers for dosing this gap. Interviews with 47 physicians and pharmacists who were liaised to drug regulation through their role in the pre- and post-marketing shaping of new cardiovascular drugs. Data were analyzed using methods of grounded theory and analytical evaluations. Six core issues were identified that referred to the standards in drug regulation, the organization of the regulatory system, and conflicting interests. Pre-marketing trials should focus more on populations and research questions relevant to medical practice. In particular, variability in drug responses between subgroups of patients and demonstration of effectiveness should become major principles in drug regulation. An interactive post-marketing process in which public interests are represented was considered necessary to further guide research and development according to the needs in daily practice. Strategies for change could be applied within the present system of drug regulation, or affect its basic principles. Regulatory authorities were primarily identified to initiate changes, but many other parties should be involved. Barriers for change were identified regarding differences in interests between parties, organizational matters, and with respect to broader healthcare policies. Based on the respondents' opinions, there is a need to focus regulatory standards more on the needs in medical practice. Therefore, regulatory authorities should further develop their influence in the pre- and post-marketing drug development process, together with other parties involved, in order to bridge the gap between clinical research and medical practice.

Evaluating Quality of Decision-Making Processes in Medicines' Development, Regulatory Review, and Health Technology Assessment: A Systematic Review of the Literature.

PubMed

Bujar, Magdalena; McAuslane, Neil; Walker, Stuart R; Salek, Sam

2017-01-01

Introduction: Although pharmaceutical companies, regulatory authorities, and health technology assessment (HTA) agencies have been increasingly using decision-making frameworks, it is not certain whether these enable better quality decision making. This could be addressed by formally evaluating the quality of decision-making process within those organizations. The aim of this literature review was to identify current techniques (tools, questionnaires, surveys, and studies) for measuring the quality of the decision-making process across the three stakeholders. Methods: Using MEDLINE, Web of Knowledge, and other Internet-based search engines, a literature review was performed to systematically identify techniques for assessing quality of decision making in medicines development, regulatory review, and HTA. A structured search was applied using key words and a secondary review was carried out. In addition, the measurement properties of each technique were assessed and compared. Ten Quality Decision-Making Practices (QDMPs) developed previously were then used as a framework for the evaluation of techniques identified in the review. Due to the variation in studies identified, meta-analysis was inappropriate. Results: This review identified 13 techniques, where 7 were developed specifically to assess decision making in medicines' development, regulatory review, or HTA; 2 examined corporate decision making, and 4 general decision making. Regarding how closely each technique conformed to the 10 QDMPs, the 13 techniques assessed a median of 6 QDMPs, with a mode of 3 QDMPs. Only 2 techniques evaluated all 10 QDMPs, namely the Organizational IQ and the Quality of Decision Making Orientation Scheme (QoDoS), of which only one technique, QoDoS could be applied to assess decision making of both individuals and organizations, and it possessed generalizability to capture issues relevant to companies as well as regulatory authorities. Conclusion: This review confirmed a general paucity of research in this area, particularly regarding the development and systematic application of techniques for evaluating quality decision making, with no consensus around a gold standard. This review has identified QoDoS as the most promising available technique for assessing decision making in the lifecycle of medicines and the next steps would be to further test its validity, sensitivity, and reliability.

Screening Methodologies to Support Risk and Technology Reviews (RTR): A Case Study Analysis

EPA Science Inventory

The Clean Air Act establishes a two-stage regulatory process for addressing emissions of hazardous air pollutants (HAPs) from stationary sources. In the first stage, the Act requires the EPA to develop technology-based standards for categories of industrial sources. We have lar...

Effects of chlorpyrifos and TCP on human kidney cells using toxicity testing and proteomics

EPA Science Inventory

An Adverse Outcome Pathway (AOP) is a conceptual framework to apply molecular pathway-based data for use in risk assessment and regulatory decision support. The development of AOPs requires data on the effects of chemicals on biological processes (i.e., molecular initiating event...

Emotion and Cognition: An Intricately Bound Developmental Process

ERIC Educational Resources Information Center

Bell, Martha Ann; Wolfe, Christy D.

2004-01-01

Regulatory aspects of development can best be understood by research that conceptualizes relations between cognition and emotion. The neural mechanisms associated with regulatory processes may be the same as those associated with higher order cognitive processes. Thus, from a developmental cognitive neuroscience perspective, emotion and cognition…

Lorcaserin: drug profile and illustrative model of the regulatory challenges of weight-loss drug development.

PubMed

Bays, Harold E

2011-03-01

Lorcaserin is a selective 5-hydroxytryptamine receptor 2c agonist developed as a weight-loss drug. Phase II and III clinical trials support lorcaserin as not only reducing adiposity (i.e., fat mass), but also as improving the metabolic diseases commonly associated with adiposopathy (i.e., fat dysfunction). At the time of this writing, regulatory processes continue towards evaluating lorcaserin as a potentially marketed weight-loss and weight-maintenance agent. Some of the challenges facing lorcaserin are similar to the difficulties encountered by all investigational weight-loss therapeutic agents, which include evolving paths towards approval. While important for clinicians to understand approval hurdles for all therapeutics, it is especially critical for researchers and developers to grasp the unique regulatory complexities of anti-obesity agents. This article profiles lorcaserin as an illustrative example of general drug development regulatory processes, and specifically details the unique challenge of weight-loss drug development.

Use of physiologically relevant biopharmaceutics tools within the pharmaceutical industry and in regulatory sciences: Where are we now and what are the gaps?

PubMed

Flanagan, Talia; Van Peer, Achiel; Lindahl, Anders

2016-08-25

Regulatory interactions are an important part of the drug development and licensing process. A survey on the use of biopharmaceutical tools for regulatory purposes has been carried out within the industry community of the EU project OrBiTo within Innovative Medicines Initiative (IMI). The aim was to capture current practice and experience in using in vitro and in silico biopharmaceutics tools at various stages of development, what barriers exist or are perceived, and to understand the current gaps in regulatory biopharmaceutics. The survey indicated that biorelevant dissolution testing and physiologically based modelling and simulation are widely applied throughout development to address a number of biopharmaceutics issues. However, data from these in vitro and in silico predictive biopharmaceutics tools are submitted to regulatory authorities far less often than they are used for internal risk assessment and decision making. This may prevent regulators from becoming familiar with these tools and how they are applied in industry, and limits the opportunities for biopharmaceutics scientists working in industry to understand the acceptability of these tools in the regulatory environment. It is anticipated that the advanced biopharmaceutics tools and understanding delivered in the next years by OrBiTo and other initiatives in the area of predictive tools will also be of value in the regulatory setting, and provide a basis for more informed and confident biopharmaceutics risk assessment and regulatory decision making. To enable the regulatory potential of predictive biopharmaceutics tools to be realized, further scientific dialogue is needed between industry, regulators and scientists in academia, and more examples need to be published to demonstrate the applicability of these tools. Copyright © 2016 Elsevier B.V. All rights reserved.

A Framework for Integrating Environmental Justice in Regulatory Analysis

PubMed Central

Nweke, Onyemaechi C.

2011-01-01

With increased interest in integrating environmental justice into the process for developing environmental regulations in the United States, analysts and decision makers are confronted with the question of what methods and data can be used to assess disproportionate environmental health impacts. However, as a first step to identifying data and methods, it is important that analysts understand what information on equity impacts is needed for decision making. Such knowledge originates from clearly stated equity objectives and the reflection of those objectives throughout the analytical activities that characterize Regulatory Impact Analysis (RIA), a process that is traditionally used to inform decision making. The framework proposed in this paper advocates structuring analyses to explicitly provide pre-defined output on equity impacts. Specifically, the proposed framework emphasizes: (a) defining equity objectives for the proposed regulatory action at the onset of the regulatory process, (b) identifying specific and related sub-objectives for key analytical steps in the RIA process, and (c) developing explicit analytical/research questions to assure that stated sub-objectives and objectives are met. In proposing this framework, it is envisioned that information on equity impacts informs decision-making in regulatory development, and that this is achieved through a systematic and consistent approach that assures linkages between stated equity objectives, regulatory analyses, selection of policy options, and the design of compliance and enforcement activities. PMID:21776235

International STakeholder NETwork (ISTNET): Creating a ...

EPA Pesticide Factsheets

A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test sys-tems and methods on the other hand. Alignment of academically and industrially-driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISNET) in DNT testing. The first meeting of ISTNET was held in Zur-ich on 23-24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems develop-ment according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a roadmap towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and address-ing the transit

Adaptation of the quality by design concept in early pharmaceutical development of an intranasal nanosized formulation.

PubMed

Pallagi, Edina; Ambrus, Rita; Szabó-Révész, Piroska; Csóka, Ildikó

2015-08-01

Regulatory science based pharmaceutical development and product manufacturing is highly recommended by the authorities nowadays. The aim of this study was to adapt regulatory science even in the nano-pharmaceutical early development. Authors applied the quality by design (QbD) concept in the early development phase of nano-systems, where the illustration material was meloxicam. The meloxicam nanoparticles produced by co-grinding method for nasal administration were studied according to the QbD policy and the QbD based risk assessment (RA) was performed. The steps were implemented according to the relevant regulatory guidelines (quality target product profile (QTPP) determination, selection of critical quality attributes (CQAs) and critical process parameters (CPPs)) and a special software (Lean QbD Software(®)) was used for the RA, which represents a novelty in this field. The RA was able to predict and identify theoretically the factors (e.g. sample composition, production method parameters, etc.) which have the highest impact on the desired meloxicam-product quality. The results of the practical research justified the theoretical prediction. This method can improve pharmaceutical nano-developments by achieving shorter development time, lower cost, saving human resource efforts and more effective target-orientation. It makes possible focusing the resources on the selected parameters and area during the practical product development. Copyright © 2015 Elsevier B.V. All rights reserved.

Validation of biomarkers to predict response to immunotherapy in cancer: Volume II - clinical validation and regulatory considerations.

PubMed

Dobbin, Kevin K; Cesano, Alessandra; Alvarez, John; Hawtin, Rachael; Janetzki, Sylvia; Kirsch, Ilan; Masucci, Giuseppe V; Robbins, Paul B; Selvan, Senthamil R; Streicher, Howard Z; Zhang, Jenny; Butterfield, Lisa H; Thurin, Magdalena

2016-01-01

There is growing recognition that immunotherapy is likely to significantly improve health outcomes for cancer patients in the coming years. Currently, while a subset of patients experience substantial clinical benefit in response to different immunotherapeutic approaches, the majority of patients do not but are still exposed to the significant drug toxicities. Therefore, a growing need for the development and clinical use of predictive biomarkers exists in the field of cancer immunotherapy. Predictive cancer biomarkers can be used to identify the patients who are or who are not likely to derive benefit from specific therapeutic approaches. In order to be applicable in a clinical setting, predictive biomarkers must be carefully shepherded through a step-wise, highly regulated developmental process. Volume I of this two-volume document focused on the pre-analytical and analytical phases of the biomarker development process, by providing background, examples and "good practice" recommendations. In the current Volume II, the focus is on the clinical validation, validation of clinical utility and regulatory considerations for biomarker development. Together, this two volume series is meant to provide guidance on the entire biomarker development process, with a particular focus on the unique aspects of developing immune-based biomarkers. Specifically, knowledge about the challenges to clinical validation of predictive biomarkers, which has been gained from numerous successes and failures in other contexts, will be reviewed together with statistical methodological issues related to bias and overfitting. The different trial designs used for the clinical validation of biomarkers will also be discussed, as the selection of clinical metrics and endpoints becomes critical to establish the clinical utility of the biomarker during the clinical validation phase of the biomarker development. Finally, the regulatory aspects of submission of biomarker assays to the U.S. Food and Drug Administration as well as regulatory considerations in the European Union will be covered.

78 FR 44193 - Introduction to the Unified Agenda of Federal Regulatory and Deregulatory Actions

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-23

... regulatory agendas in the Federal Register describing regulatory actions they are developing that may have a... officials early in the process of developing the regulation. In addition, the agency must provide to the... result, in an annual effect on the economy of $100 million or more or meets other criteria specified in...

A drug's life: the pathway to drug approval.

PubMed

Keng, Michael K; Wenzell, Candice M; Sekeres, Mikkael A

2013-10-01

In the United States, drugs and medical devices are regulated by the US Food and Drug Administration (FDA). A drug must undergo rigorous testing prior to marketing to and medical use by the general public. The FDA grants marketing approval for drug products based on a comprehensive review of safety and efficacy data. This review article explains the history behind the establishment of the FDA and examines the historical legislation and approval processes for drugs, specifically in the fields of medical oncology and hematology. The agents imatinib (Gleevec, Novartis) and decitabine (Dacogen, Eisai) are used to illustrate both the current FDA regulatory process-specifically the orphan drug designation and accelerated approval process-and why decitabine failed to gain an indication for acute myeloid leukemia. The purpose and construct of the Oncologic Drugs Advisory Committee are also discussed, along with examples of 2 renal cell cancer drugs-axitinib (Inlyta, Pfizer) and tivozanib-that used progression-free survival as an endpoint. Regulatory approval of oncology drugs is the cornerstone of the development of new treatment agents and modalities, which lead to improvements in the standard of cancer care. The future landscape of drug development and regulatory approval will be influenced by the new breakthrough therapy designation, and choice of drug will be guided by genomic insights.

Patient Experience Data in US Food and Drug Administration (FDA) Regulatory Decision Making:: A Policy Process Perspective.

PubMed

Kuehn, Carrie M

2018-01-01

The influence of patient advocates on FDA regulatory decision making has increased. Despite enhanced engagement with FDA, there remain challenges to achieving the regulatory goals of patients within FDA's regulatory framework. Gaps exist between patient advocates' knowledge of the agency's processes and FDA's need for rigorous, clinically meaningful patient experience data. This study examined the policy process in which patient experience data are collected by patient advocates and provided to FDA for regulatory decision making. Semistructured, narrative interviews were conducted with 14 professionals working in patient advocacy or at FDA. The purpose was to examine, in depth, participants' perceptions and experiences regarding this new regulatory process. Interviews were coded and examined for themes. The use of patient experience data by FDA is an evolving regulatory process. Participants identified a number of barriers and contributors to regulatory success. Well-organized and sophisticated patient advocacy groups with access to scientific and policy expertise are more likely to find success meeting FDA's patient experience data requirements. A conceptual model of this regulatory process was developed. Use of patient experience data by FDA has the potential to positively influence the regulation of medical products in the United States. Success within this new regulatory process will depend on clear guidance from FDA regarding the collection, analysis, and use of patient experience data. Patient advocacy groups must enhance internal capacity and expertise while engaging in substantive collaborations with FDA and other stakeholders in order to meaningfully contribute to the regulatory review of new therapeutics.

Steering healthcare service delivery: a regulatory perspective.

PubMed

Prakash, Gyan

2015-01-01

The purpose of this paper is to explore regulation in India's healthcare sector and makes recommendations needed for enhancing the healthcare service. The literature was reviewed to understand healthcare's regulatory context. To understand the current healthcare system, qualitative data were collected from state-level officials, public and private hospital staff. A patient survey was performed to assess service quality (QoS). Regulation plays a central role in driving healthcare QoS. India needs to strengthen market and institutional co-production based approaches for steering its healthcare in which delivery processes are complex and pose different challenges. This study assesses current healthcare regulation in an Indian state and presents a framework for studying and strengthening regulation. Agile regulation should be based on service delivery issues (pull approach) rather than monitoring and sanctions based regulatory environment (push approach). Healthcare pitfalls across the world seem to follow similar follies. India's complexity and experience is useful for emerging and developed economies. The author reviewed around 70 publications and synthesised them in healthcare regulatory contexts. Patient's perception of private providers could be a key input towards steering regulation. Identifying gaps across QoS dimensions would be useful in taking corrective measures.

Critical thinking as a self-regulatory process component in teaching and learning.

PubMed

Phan, Huy P

2010-05-01

This article presents a theoretically grounded model of critical thinking and self-regulation in the context of teaching and learning. Critical thinking, deriving from an educational psychology perspective is a complex process of reflection that helps individuals become more analytical in their thinking and professional development. My conceptualisation in this discussion paper argues that both theoretical orientations (critical thinking and self-regulation) operate in a dynamic interactive system of teaching and learning. My argument, based on existing research evidence, suggests two important points: (i) critical thinking acts as another cognitive strategy of self-regulation that learners use in their learning, and (ii) critical thinking may be a product of various antecedents such as different self-regulatory strategies.

A genomic regulatory network for development

NASA Technical Reports Server (NTRS)

Davidson, Eric H.; Rast, Jonathan P.; Oliveri, Paola; Ransick, Andrew; Calestani, Cristina; Yuh, Chiou-Hwa; Minokawa, Takuya; Amore, Gabriele; Hinman, Veronica; Arenas-Mena, Cesar;

COST EFFECTIVE REGULATORY APPROACHES TO ENHANCE DOMESTIC OIL & GAS PRODUCTION AND ENSURE THE PROTECTION OF THE ENVIRONMENT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ben Grunewald; Paul Jehn; Tom Gillespie

The Environmental Information Management Suite/Risk Based Data Management System (EIMS/RBDMS) and Cost Effective Regulatory Approach (CERA) programs continue to be successful. All oil and gas state regulatory programs participate in these efforts. Significant accomplishments include: streamline regulatory approaches, enhancing environmental protection, and making oil and gas data available via the Internet. Oil and gas companies worldwide now have access to data on state web sites. This reduces the cost of exploration and enables companies to develop properties in areas that would have been cost prohibited for exploration. Early in project, GWPC and State Oil and Gas agencies developed the EIMSmore » and CERA strategic plan to prioritize long term development and implementation. The planning process identifies electronic commerce and coal bed methane as high priorities. The group has involved strategic partners in industry and government to develop a common data exchange process. Technical assistance to Alaska continues to improve their program management capabilities. New initiatives in Alaska include the development of an electronic permit tracking system. This system allows managers to expedite the permitting process. Nationwide, the RBDMS system is largely completed with 22 states and one Indian Nation now using this nationally accepted data management system. Additional remaining tasks include routine maintenance and the installation of the program upon request for the remaining oil and gas states. The GWPC in working with the BLM and MMS to develop an XML schema to facilitate electronic permitting and reporting (Appendix A, B, and C). This is a significant effort and, in years to come, will increase access to federal lands by reducing regulatory barriers. The new initiatives are coal bed methane and e-commerce. The e-commerce program will provide industry and BLM/MMS access to the millions of data points housed in the RBDMS system. E-commerce will streamline regulatory approaches and allow small operators to produce energy from areas that have become sub-economic for the major producers. The GWPC is working with states to develop a coal bed methane program, which will both manage the data and develop a public education program on the benefits of produced water. The CERA program benefits all oil and gas states by reducing the cost of regulatory compliance, increasing environmental protection, and providing industry and regulatory agencies a discussion forum. Activities included many small and large group forum settings for discussions of technical and policy issues as well as the ongoing State Class II UIC peer review effort. The accomplishments detailed in this report will be the basis for the next initiative which is RBDMS On-Line. RBDMS On-Line will combine data mining, electronic permitting and electronic reporting with .net technology. Industry, BLM, GWPC and all Oil and Gas states are partnering this effort.« less

Creating an effort tracking tool to improve therapeutic cancer clinical trials workload management and budgeting.

PubMed

James, Pam; Bebee, Patty; Beekman, Linda; Browning, David; Innes, Mathew; Kain, Jeannie; Royce-Westcott, Theresa; Waldinger, Marcy

2011-11-01

Quantifying data management and regulatory workload for clinical research is a difficult task that would benefit from a robust tool to assess and allocate effort. As in most clinical research environments, The University of Michigan Comprehensive Cancer Center (UMCCC) Clinical Trials Office (CTO) struggled to effectively allocate data management and regulatory time with frequently inaccurate estimates of how much time was required to complete the specific tasks performed by each role. In a dynamic clinical research environment in which volume and intensity of work ebbs and flows, determining requisite effort to meet study objectives was challenging. In addition, a data-driven understanding of how much staff time was required to complete a clinical trial was desired to ensure accurate trial budget development and effective cost recovery. Accordingly, the UMCCC CTO developed and implemented a Web-based effort-tracking application with the goal of determining the true costs of data management and regulatory staff effort in clinical trials. This tool was developed, implemented, and refined over a 3-year period. This article describes the process improvement and subsequent leveling of workload within data management and regulatory that enhanced the efficiency of UMCCC's clinical trials operation.

Prediction of regulatory gene pairs using dynamic time warping and gene ontology.

PubMed

Yang, Andy C; Hsu, Hui-Huang; Lu, Ming-Da; Tseng, Vincent S; Shih, Timothy K

2014-01-01

Selecting informative genes is the most important task for data analysis on microarray gene expression data. In this work, we aim at identifying regulatory gene pairs from microarray gene expression data. However, microarray data often contain multiple missing expression values. Missing value imputation is thus needed before further processing for regulatory gene pairs becomes possible. We develop a novel approach to first impute missing values in microarray time series data by combining k-Nearest Neighbour (KNN), Dynamic Time Warping (DTW) and Gene Ontology (GO). After missing values are imputed, we then perform gene regulation prediction based on our proposed DTW-GO distance measurement of gene pairs. Experimental results show that our approach is more accurate when compared with existing missing value imputation methods on real microarray data sets. Furthermore, our approach can also discover more regulatory gene pairs that are known in the literature than other methods.

Adolescent transformations of behavioral and neural processes as potential targets for prevention.

PubMed

Eldreth, Dana; Hardin, Michael G; Pavletic, Nevia; Ernst, Monique

2013-06-01

Adolescence is a transitional period in development that is marked by a distinct, typical behavioral profile of high rates of exploration, novelty-seeking, and emotional lability. While these behaviors generally assist the adolescent transition to independence, they can also confer vulnerability for excessive risk-taking and psychopathology, particularly in the context of specific environmental or genetic influences. As prevention research depends on the identification of targets of vulnerability, the following review will discuss the interplay among motivational systems including reward-related, avoidance-related, and regulatory processes in typical and atypical adolescent development. Each set of processes will be discussed in relation to their underlying neural correlates and distinct developmental trajectories. Evidence suggests that typical adolescent behavior and the risk for atypical development are mediated by heightened adolescent responsiveness of reward-related and avoidance-related systems under specific conditions, concurrent with poor modulation by immature regulatory processes. Finally, we will propose strategies to exploit heightened reward processing to reinforce inhibitory control, which is an essential component of regulatory processes in prevention interventions.

Evolving Regulatory Processes Used by Students and Experts in the Acquiring of Improvisational Skills: A Qualitative Study

ERIC Educational Resources Information Center

de Bruin, Leon R.

2018-01-01

The way an improviser practices is a vital and significant aspect to a musician's means and capacities of expression. Expert music performers utilize extensive self-regulatory processes involving planning, strategic development, and systemized approaches to learning and reflective practice. Scholars posit that these processes are constructivist…

Japan-Specific Key Regulatory Aspects for Development of New Biopharmaceutical Drug Products.

PubMed

Desai, Kashappa Goud; Obayashi, Hirokazu; Colandene, James D; Nesta, Douglas P

2018-03-28

Japan represents the third largest pharmaceutical market in the world. Developing a new biopharmaceutical drug product for the Japanese market is a top business priority for global pharmaceutical companies while aligning with ethical drivers to treat more patients in need. Understanding Japan-specific key regulatory requirements is essential to achieve successful approvals. Understanding the full context of Japan-specific regulatory requirements/expectations is challenging to global pharmaceutical companies due to differences in language and culture. This article summarizes key Japan-specific regulatory aspects/requirements/expectations applicable to new drug development, approval, and postapproval phases. Formulation excipients should meet Japan compendial requirements with respect to the type of excipient, excipient grade, and excipient concentration. Preclinical safety assessments needed to support clinical phases I, II, and III development are summarized. Japanese regulatory authorities have taken appropriate steps to consider foreign clinical data, thereby enabling accelerated drug development and approval in Japan. Other important topics summarized in this article include: Japan new drug application-specific bracketing strategies for critical and noncritical aspects of the manufacturing process, regulatory requirements related to stability studies, release specifications and testing methods, standard processes involved in pre and postapproval inspections, management of postapproval changes, and Japan regulatory authority's consultation services available to global pharmaceutical companies. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Efficient experimental design for uncertainty reduction in gene regulatory networks.

PubMed

Dehghannasiri, Roozbeh; Yoon, Byung-Jun; Dougherty, Edward R

2015-01-01

An accurate understanding of interactions among genes plays a major role in developing therapeutic intervention methods. Gene regulatory networks often contain a significant amount of uncertainty. The process of prioritizing biological experiments to reduce the uncertainty of gene regulatory networks is called experimental design. Under such a strategy, the experiments with high priority are suggested to be conducted first. The authors have already proposed an optimal experimental design method based upon the objective for modeling gene regulatory networks, such as deriving therapeutic interventions. The experimental design method utilizes the concept of mean objective cost of uncertainty (MOCU). MOCU quantifies the expected increase of cost resulting from uncertainty. The optimal experiment to be conducted first is the one which leads to the minimum expected remaining MOCU subsequent to the experiment. In the process, one must find the optimal intervention for every gene regulatory network compatible with the prior knowledge, which can be prohibitively expensive when the size of the network is large. In this paper, we propose a computationally efficient experimental design method. This method incorporates a network reduction scheme by introducing a novel cost function that takes into account the disruption in the ranking of potential experiments. We then estimate the approximate expected remaining MOCU at a lower computational cost using the reduced networks. Simulation results based on synthetic and real gene regulatory networks show that the proposed approximate method has close performance to that of the optimal method but at lower computational cost. The proposed approximate method also outperforms the random selection policy significantly. A MATLAB software implementing the proposed experimental design method is available at http://gsp.tamu.edu/Publications/supplementary/roozbeh15a/.

Efficient experimental design for uncertainty reduction in gene regulatory networks

PubMed Central

2015-01-01

Background An accurate understanding of interactions among genes plays a major role in developing therapeutic intervention methods. Gene regulatory networks often contain a significant amount of uncertainty. The process of prioritizing biological experiments to reduce the uncertainty of gene regulatory networks is called experimental design. Under such a strategy, the experiments with high priority are suggested to be conducted first. Results The authors have already proposed an optimal experimental design method based upon the objective for modeling gene regulatory networks, such as deriving therapeutic interventions. The experimental design method utilizes the concept of mean objective cost of uncertainty (MOCU). MOCU quantifies the expected increase of cost resulting from uncertainty. The optimal experiment to be conducted first is the one which leads to the minimum expected remaining MOCU subsequent to the experiment. In the process, one must find the optimal intervention for every gene regulatory network compatible with the prior knowledge, which can be prohibitively expensive when the size of the network is large. In this paper, we propose a computationally efficient experimental design method. This method incorporates a network reduction scheme by introducing a novel cost function that takes into account the disruption in the ranking of potential experiments. We then estimate the approximate expected remaining MOCU at a lower computational cost using the reduced networks. Conclusions Simulation results based on synthetic and real gene regulatory networks show that the proposed approximate method has close performance to that of the optimal method but at lower computational cost. The proposed approximate method also outperforms the random selection policy significantly. A MATLAB software implementing the proposed experimental design method is available at http://gsp.tamu.edu/Publications/supplementary/roozbeh15a/. PMID:26423515

Pharmaceutical product development: A quality by design approach

PubMed Central

Pramod, Kannissery; Tahir, M. Abu; Charoo, Naseem A.; Ansari, Shahid H.; Ali, Javed

2016-01-01

The application of quality by design (QbD) in pharmaceutical product development is now a thrust area for the regulatory authorities and the pharmaceutical industry. International Conference on Harmonization and United States Food and Drug Administration (USFDA) emphasized the principles and applications of QbD in pharmaceutical development in their guidance for the industry. QbD attributes are addressed in question-based review, developed by USFDA for chemistry, manufacturing, and controls section of abbreviated new drug applications. QbD principles, when implemented, lead to a successful product development, subsequent prompt regulatory approval, reduce exhaustive validation burden, and significantly reduce post-approval changes. The key elements of QbD viz., target product quality profile, critical quality attributes, risk assessments, design space, control strategy, product lifecycle management, and continual improvement are discussed to understand the performance of dosage forms within design space. Design of experiments, risk assessment tools, and process analytical technology are also discussed for their role in QbD. This review underlines the importance of QbD in inculcating science-based approach in pharmaceutical product development. PMID:27606256

Pharmaceutical product development: A quality by design approach.

PubMed

Pramod, Kannissery; Tahir, M Abu; Charoo, Naseem A; Ansari, Shahid H; Ali, Javed

2016-01-01

The application of quality by design (QbD) in pharmaceutical product development is now a thrust area for the regulatory authorities and the pharmaceutical industry. International Conference on Harmonization and United States Food and Drug Administration (USFDA) emphasized the principles and applications of QbD in pharmaceutical development in their guidance for the industry. QbD attributes are addressed in question-based review, developed by USFDA for chemistry, manufacturing, and controls section of abbreviated new drug applications. QbD principles, when implemented, lead to a successful product development, subsequent prompt regulatory approval, reduce exhaustive validation burden, and significantly reduce post-approval changes. The key elements of QbD viz., target product quality profile, critical quality attributes, risk assessments, design space, control strategy, product lifecycle management, and continual improvement are discussed to understand the performance of dosage forms within design space. Design of experiments, risk assessment tools, and process analytical technology are also discussed for their role in QbD. This review underlines the importance of QbD in inculcating science-based approach in pharmaceutical product development.

International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes.

PubMed

Bal-Price, Anna; Crofton, Kevin M; Leist, Marcel; Allen, Sandra; Arand, Michael; Buetler, Timo; Delrue, Nathalie; FitzGerald, Rex E; Hartung, Thomas; Heinonen, Tuula; Hogberg, Helena; Bennekou, Susanne Hougaard; Lichtensteiger, Walter; Oggier, Daniela; Paparella, Martin; Axelstad, Marta; Piersma, Aldert; Rached, Eva; Schilter, Benoît; Schmuck, Gabriele; Stoppini, Luc; Tongiorgi, Enrico; Tiramani, Manuela; Monnet-Tschudi, Florianne; Wilks, Martin F; Ylikomi, Timo; Fritsche, Ellen

2015-02-01

A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISTNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23-24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling.

On the Concept of Cis-regulatory Information: From Sequence Motifs to Logic Functions

NASA Astrophysics Data System (ADS)

Tarpine, Ryan; Istrail, Sorin

The regulatory genome is about the “system level organization of the core genomic regulatory apparatus, and how this is the locus of causality underlying the twin phenomena of animal development and animal evolution” (E.H. Davidson. The Regulatory Genome: Gene Regulatory Networks in Development and Evolution, Academic Press, 2006). Information processing in the regulatory genome is done through regulatory states, defined as sets of transcription factors (sequence-specific DNA binding proteins which determine gene expression) that are expressed and active at the same time. The core information processing machinery consists of modular DNA sequence elements, called cis-modules, that interact with transcription factors. The cis-modules “read” the information contained in the regulatory state of the cell through transcription factor binding, “process” it, and directly or indirectly communicate with the basal transcription apparatus to determine gene expression. This endowment of each gene with the information-receiving capacity through their cis-regulatory modules is essential for the response to every possible regulatory state to which it might be exposed during all phases of the life cycle and in all cell types. We present here a set of challenges addressed by our CYRENE research project aimed at studying the cis-regulatory code of the regulatory genome. The CYRENE Project is devoted to (1) the construction of a database, the cis-Lexicon, containing comprehensive information across species about experimentally validated cis-regulatory modules; and (2) the software development of a next-generation genome browser, the cis-Browser, specialized for the regulatory genome. The presentation is anchored on three main computational challenges: the Gene Naming Problem, the Consensus Sequence Bottleneck Problem, and the Logic Function Inference Problem.

Needs-Based Innovation in Interventional Radiology: The Biodesign Process.

PubMed

Steinberger, Jonathan D; Denend, Lyn; Azagury, Dan E; Brinton, Todd J; Makower, Josh; Yock, Paul G

2017-06-01

There are many possible mechanisms for innovation and bringing new technology into the marketplace. The Stanford Biodesign innovation process is based in a deep understanding of clinical unmet needs as the basis for focused ideation and development. By identifying and vetting a compelling unmet need, the aspiring innovator can "derisk" a project and maximize chances for successful development in an increasingly challenging regulatory and economic environment. As a specialty founded by tinkerers, with a history of disruptive innovation that has yielded countless new ways of delivering care with minimal invasiveness, lower morbidity, and lower cost, interventional radiologists are uniquely well positioned to identify unmet needs and develop novel solutions free of dogmatic convention. Copyright © 2017 Elsevier Inc. All rights reserved.

The early career researcher's toolkit: translating tissue engineering, regenerative medicine and cell therapy products.

PubMed

Rafiq, Qasim A; Ortega, Ilida; Jenkins, Stuart I; Wilson, Samantha L; Patel, Asha K; Barnes, Amanda L; Adams, Christopher F; Delcassian, Derfogail; Smith, David

2015-11-01

Although the importance of translation for the development of tissue engineering, regenerative medicine and cell-based therapies is widely recognized, the process of translation is less well understood. This is particularly the case among some early career researchers who may not appreciate the intricacies of translational research or make decisions early in development which later hinders effective translation. Based on our own research and experiences as early career researchers involved in tissue engineering and regenerative medicine translation, we discuss common pitfalls associated with translational research, providing practical solutions and important considerations which will aid process and product development. Suggestions range from effective project management, consideration of key manufacturing, clinical and regulatory matters and means of exploiting research for successful commercialization.

GIS-assisted spatial analysis for urban regulatory detailed planning: designer's dimension in the Chinese code system

NASA Astrophysics Data System (ADS)

Yu, Yang; Zeng, Zheng

2009-10-01

By discussing the causes behind the high amendments ratio in the implementation of urban regulatory detailed plans in China despite its law-ensured status, the study aims to reconcile conflict between the legal authority of regulatory detailed planning and the insufficient scientific support in its decision-making and compilation by introducing into the process spatial analysis based on GIS technology and 3D modeling thus present a more scientific and flexible approach to regulatory detailed planning in China. The study first points out that the current compilation process of urban regulatory detailed plan in China employs mainly an empirical approach which renders it constantly subjected to amendments; the study then discusses the need and current utilization of GIS in the Chinese system and proposes the framework of a GIS-assisted 3D spatial analysis process from the designer's perspective which can be regarded as an alternating processes between the descriptive codes and physical design in the compilation of regulatory detailed planning. With a case study of the processes and results from the application of the framework, the paper concludes that the proposed framework can be an effective instrument which provides more rationality, flexibility and thus more efficiency to the compilation and decision-making process of urban regulatory detailed plan in China.

Medical device development.

PubMed

Panescu, Dorin

2009-01-01

The development of a successful medical product requires not only engineering design efforts, but also clinical, regulatory, marketing and business expertise. This paper reviews items related to the process of designing medical devices. It discusses the steps required to take a medical product idea from concept, through development, verification and validation, regulatory approvals and market release.

[Strengthening health regulation in the Americas: regulatory authorities of regional reference].

PubMed

Ojeda, Lisette Pérez; Cristiá, Rafael Pérez

2016-05-01

Health technology regulation and quality assurance are critical to the development of national pharmaceutical policies, and implementing these actions is the responsibility of national regulatory authorities, whose level of development and maturity affect the quality, safety, and effectiveness of the products made available to the public. On the initiative of the regulatory authorities themselves, together with the Pan American Health Organization, the Region of the Americas promotes the strengthening of health regulation through an evaluation and certification process that allows for the designation of regulatory authorities of regional reference for drugs and biological products. Over the period from its implementation to the present, six authorities have been certified and one is in the process of obtaining certification. These authorities work jointly and promote dialogue and regulatory convergence, information-sharing to facilitate regulatory decision making, and regional cooperation to support the establishment of other authorities in the Region--actions having direct impact on access to effective and quality-assured health technologies. Their combined efforts have led to the recognition of this process of evaluation and certification by the World Health Organization (WHO). Among the actions resulting from the International Consultation on Regulatory Systems Strengthening, WHO recommended taking a close look at this model to assess its potential scale-up at the global level.

A planning support system to optimize approval of private housing development projects

NASA Astrophysics Data System (ADS)

Hussnain, M. Q.; Wakil, K.; Waheed, A.; Tahir, A.

2016-06-01

Out of 182 million population of Pakistan, 38% reside in urban areas having an average growth rate of 1.6%, raising the urban housing demand significantly. Poor state response to fulfil the housing needs has resulted in a mushroom growth of private housing schemes (PHS) over the years. Consequently, only in five major cities of Punjab, there are 383 legal and 150 illegal private housing development projects against 120 public sector housing schemes. A major factor behind the cancerous growth of unapproved PHS is the prolonged and delayed approval process in concerned approval authorities requiring 13 months on average. Currently, manual and paper-based approaches are used for vetting and for granting the permission which is highly subjective and non-transparent. This study aims to design a flexible planning support system (PSS) to optimize the vetting process of PHS projects under any development authority in Pakistan by reducing time and cost required for site and documents investigations. Relying on the review of regulatory documents and interviews with professional planners and land developers, this study describes the structure of a PSS developed using open- source geo-spatial tools such as OpenGeo Suite, PHP, and PostgreSQL. It highlights the development of a Knowledge Module (based on regulatory documents) containing equations related to scheme type, size (area), location, access road, components of layout plan, planning standards and other related approval checks. Furthermore, it presents the architecture of the database module and system data requirements categorized as base datasets (built-in part of PSS) and input datasets (related to the housing project under approval). It is practically demonstrated that developing a customized PSS to optimize PHS approval process in Pakistan is achievable with geospatial technology. With the provision of such a system, the approval process for private housing schemes not only becomes quicker and user-friendly but also transparent.

Early dialogue with health technology assessment bodies: a European perspective.

PubMed

Cuche, Matthieu; Beckerman, Rachel; Chowdhury, Cyrus A; van Weelden, Marije A

2014-12-01

Evidence requirements may differ across HTA bodies, and so pharmaceutical companies must plan to synergize their evidence generation strategy, across global regulatory and HTA bodies. Until recently, companies had no official platform to discuss the clinical development of a drug with HTA bodies; however, this is changing. To achieve broad usage in the EU, products must achieve both regulatory and reimbursement approval, the latter of which is based on HTA appraisal in many markets. The objective of this study is to present and evaluate the different options available for early HTA consultation (during drug development/Phase III) in the major European markets from the industry perspective. An exploratory (nonsystematic) literature review was performed to identify the European markets offering early HTA consultations, and each process was analyzed using a set of predefined metrics that are relevant to industry (the ability to consult with the regulatory body in parallel, consultation fees, length of consultation meeting, language of consultation meeting, maximum number of pharmaceutical company employees attending, procedural timelines, nature of data for which consultative advice can be sought, the output of the process, and the ability to involve external experts). Four different types of early HTA consultation processes were identified across the major European HTA markets. The nature of these processes varied in terms of the types and number of questions that can be addressed, the length of the meeting, the reporting output, and the ability to involve external experts. The availability of various options for early HTA consultation may help to avoid a mismatch between the evidence generated by means of a product's clinical development program, and the evidence expected by HTA bodies and payers, which can facilitate the pricing and reimbursement process upon a product's market authorization.

76 FR 72220 - Incorporation of Risk Management Concepts in Regulatory Programs

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-22

... and support the adoption of improved designs or processes. \\1\\ A deterministic approach to regulation... longstanding goal to move toward more risk-informed, performance- based approaches in its regulatory programs... regulatory approach that would continue to ensure the safe and secure use of nuclear material. As part of...

75 FR 9626 - Notice of Issuance of Regulatory Guide

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-03

... maintain variables and systems that can affect the fission process, the integrity of the reactor core, the... on some other defined basis. GDC 24 requires that interconnection of the protection and control..., Regulatory Guide Development Branch, Division of Engineering, Office of Nuclear Regulatory Research. [FR Doc...

Evaluating Quality of Decision-Making Processes in Medicines' Development, Regulatory Review, and Health Technology Assessment: A Systematic Review of the Literature

PubMed Central

Bujar, Magdalena; McAuslane, Neil; Walker, Stuart R.; Salek, Sam

2017-01-01

Introduction: Although pharmaceutical companies, regulatory authorities, and health technology assessment (HTA) agencies have been increasingly using decision-making frameworks, it is not certain whether these enable better quality decision making. This could be addressed by formally evaluating the quality of decision-making process within those organizations. The aim of this literature review was to identify current techniques (tools, questionnaires, surveys, and studies) for measuring the quality of the decision-making process across the three stakeholders. Methods: Using MEDLINE, Web of Knowledge, and other Internet-based search engines, a literature review was performed to systematically identify techniques for assessing quality of decision making in medicines development, regulatory review, and HTA. A structured search was applied using key words and a secondary review was carried out. In addition, the measurement properties of each technique were assessed and compared. Ten Quality Decision-Making Practices (QDMPs) developed previously were then used as a framework for the evaluation of techniques identified in the review. Due to the variation in studies identified, meta-analysis was inappropriate. Results: This review identified 13 techniques, where 7 were developed specifically to assess decision making in medicines' development, regulatory review, or HTA; 2 examined corporate decision making, and 4 general decision making. Regarding how closely each technique conformed to the 10 QDMPs, the 13 techniques assessed a median of 6 QDMPs, with a mode of 3 QDMPs. Only 2 techniques evaluated all 10 QDMPs, namely the Organizational IQ and the Quality of Decision Making Orientation Scheme (QoDoS), of which only one technique, QoDoS could be applied to assess decision making of both individuals and organizations, and it possessed generalizability to capture issues relevant to companies as well as regulatory authorities. Conclusion: This review confirmed a general paucity of research in this area, particularly regarding the development and systematic application of techniques for evaluating quality decision making, with no consensus around a gold standard. This review has identified QoDoS as the most promising available technique for assessing decision making in the lifecycle of medicines and the next steps would be to further test its validity, sensitivity, and reliability. PMID:28443022

Capacity for ethical and regulatory review of herbal trials in developing countries: a case study of Moringa oleifera research in HIV-infected patients.

PubMed

Monera-Penduka, Tsitsi G; Maponga, Charles C; Morse, Gene D; Nhachi, Charles F B

2017-01-01

Lack of regulatory capacity limits the conduct of ethical and rigorous trials of herbal medicines in developing countries. Sharing ethical and regulatory experiences of successful herbal trials may accelerate the field while assuring human subjects protection. The methods and timelines for the ethical and regulatory review processes for the first drug regulatory authority approved herbal trial in Zimbabwe are described in this report. The national drug regulatory authority and ethics committee were engaged for pre-submission discussions. Six applications were submitted. Application procedures and communications with the various regulatory and ethics review boards were reviewed. Key issues raised and timelines for communications were summarized. There was no special framework for the approval of herbal trials. One local institutional review committee granted an exemption. Key issues raised for revision were around pre-clinical efficacy and safety data, standardization and quality assurance of the intervention as well as consenting procedures. Approval timelines ranged between eight and 72 weeks. In the absence of a defined framework for review of herbal trials, approval processes can be delayed. Dialogue between researchers and regulators is important for successful and efficient protocol approval for herbal trials in developing countries. The study was registered prospectively on August 3, 2011 with clinicaltrials.gov (NCT01410058).

Valued ecosystem components for watershed cumulative effects: an analysis of environmental impact assessments in the South Saskatchewan River watershed, Canada.

PubMed

Ball, Murray A; Noble, Bram F; Dubé, Monique G

2013-07-01

The accumulating effects of human development are threatening water quality and availability. In recognition of the constraints to cumulative effects assessment (CEA) under traditional environmental impact assessment (EIA), there is an emerging body of research dedicated to watershed-based cumulative effects assessment (WCEA). To advance the science of WCEA, however, a standard set of ecosystem components and indicators is required that can be used at the watershed scale, to inform effects-based understanding of cumulative change, and at the project scale, to inform regulatory-based project based impact assessment and mitigation. A major challenge, however, is that it is not clear how such ecosystem components and indicators for WCEA can or should be developed. This study examined the use of aquatic ecosystem components and indicators in EIA practice in the South Saskatchewan River watershed, Canada, to determine whether current practice at the project scale could be "scaled up" to support ecosystem component and indicator development for WCEA. The hierarchy of assessment components and indicators used in a sample of 35 environmental impact assessments was examined and the factors affecting aquatic ecosystem component selection and indicator use were identified. Results showed that public environmental impact statements are not necessarily publically accessible, thus limiting opportunities for data and information sharing from the project to the watershed scale. We also found no consistent terminology across the sample of impact statements, thus making comparison of assessment processes and results difficult. Regulatory compliance was found to be the dominant factor influencing the selection of ecosystem components and indicators for use in project assessment, rather than scientific reasoning, followed by the mandate of the responsible government agency for the assessment, public input to the assessment process, and preexisting water licensing arrangements external to the assessment process. The current approach to project-based assessment offered little support for WCEA initiatives. It did not provide a standard set of aquatic ecosystem components and indicators or allow the sharing of information across projects and from the project to the watershed scale. We suggest that determining priority assessment parameters for WCEA requires adoption of a standardized framework of component and indicator terminology, which can then be populated for the watershed of concern based on both watershed-based priorities and project-specific regulatory requirements. Copyright © 2012 SETAC.

Novel licensure pathways for expeditious introduction of new tuberculosis vaccines: a discussion of the adaptive licensure concept.

PubMed

Rustomjee, Roxana; Lockhart, Stephen; Shea, Jacqueline; Fourie, P Bernard; Hindle, Zoë; Steel, Gavin; Hussey, Gregory; Ginsberg, Ann; Brennan, Michael J

2014-03-01

The ultimate goal of vaccine development is licensure of a safe and efficacious product that has a well-defined manufacturing process resulting in a high quality product. In general, clinical development and regulatory approval occurs in a linear, sequential manner: Phase 1 - safety, immunogenicity; Phase 2 - immunogenicity, safety, dose ranging and preliminary efficacy; Phase 3 - definitive efficacy, safety, lot consistency; and, following regulatory approval, Phase 4 - post-marketing safety and effectiveness. For candidate TB vaccines, where correlates of protection are not yet identified, phase 2 and 3 efficacy of disease prevention trials are, by necessity, very large. Each trial would span 2-5 years, with full licensure expected only after 1 or even 2 decades of development. Given the urgent unmet need for a new TB vaccine, a satellite discussion was held at the International African Vaccinology Conference in Cape Town, South Africa in November 2012, to explore the possibility of expediting licensure by use of an "adaptive licensure" process, based on a risk/benefit assessment that is specific to regional needs informed by epidemiology. This may be appropriate for diseases such as TB, where high rates of morbidity, mortality, particularly in high disease burden countries, impose an urgent need for disease prevention. The discussion focused on two contexts: licensure within the South African regulatory environment - a high burden country where TB vaccine efficacy trials are on-going, and licensure by the United States FDA --a well-resourced regulatory agency where approval could facilitate global licensure of a novel TB vaccine. Copyright © 2013. Published by Elsevier Ltd.

Bureau of Reclamation Hydropower Lease of Power Privilege: Case Studies and Considerations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Curtis, Taylor L.; Levine, Aaron L.; McLaughlin, Kathleen

This report analyzes the U.S. Bureau of Reclamation's (Reclamation) lease of power privilege (LOPP) regulatory process for a nonfederal entity to use a Reclamation jurisdictional dam or conduit for power generation. Recent federal initiatives encouraging hydropower development at federally-owned facilities coupled with Reclamation's hydroelectric potential has led to an increased interest in powering Reclamation dams and conduits through the LOPP process. During the last five years, 23 of the 36 total LOPP projects (76 MW) have been initiated and are at some phase of the development process. Resource assessments analyzed in this report identify over 360 MW of hydroelectric potentialmore » at Reclamation-owned dams and conduits. This report provides considerations from Reclamation staff involved in the LOPP regulatory process and developers that have received an LOPP and are currently generating hydropower at a Reclamation dam or conduit. The authors also analyze LOPP regulatory processing timelines before and after the implementation of federal initiatives to streamline the LOPP process and provide case studies of hydropower projects that have obtained an LOPP.« less

Identification of regulatory network hubs that control lipid metabolism in Chlamydomonas reinhardtii

DOE PAGES

Gargouri, Mahmoud; Park, Jeong -Jin; Holguin, F. Omar; ...

2015-05-28

Microalgae-based biofuels are promising sources of alternative energy, but improvements throughout the production process are required to establish them as economically feasible. One of the most influential improvements would be a significant increase in lipid yields, which could be achieved by altering the regulation of lipid biosynthesis and accumulation. Chlamydomonas reinhardtii accumulates oil (triacylglycerols, TAG) in response to nitrogen (N) deprivation. Although a few important regulatory genes have been identified that are involved in controlling this process, a global understanding of the larger regulatory network has not been developed. In order to uncover this network in this species, a combinedmore » omics (transcriptomic, proteomic and metabolomic) analysis was applied to cells grown in a time course experiment after a shift from N-replete to N-depleted conditions. Changes in transcript and protein levels of 414 predicted transcription factors (TFs) and transcriptional regulators (TRs) were monitored relative to other genes. The TF and TR genes were thus classified by two separate measures: up-regulated versus down-regulated and early response versus late response relative to two phases of polar lipid synthesis (before and after TAG biosynthesis initiation). Lipidomic and primary metabolite profiling generated compound accumulation levels that were integrated with the transcript dataset and TF profiling to produce a transcriptional regulatory network. In conclusion, evaluation of this proposed regulatory network led to the identification of several regulatory hubs that control many aspects of cellular metabolism, from N assimilation and metabolism, to central metabolism, photosynthesis and lipid metabolism.« less

Strategic Regulatory Evaluation and Endorsement of the Hollow Fiber Tuberculosis System as a Novel Drug Development Tool.

PubMed

Romero, Klaus; Clay, Robert; Hanna, Debra

2015-08-15

The first nonclinical drug development tool (DDT) advanced by the Critical Path to TB Drug Regimens (CPTR) Initiative through a regulatory review process has been endorsed by leading global regulatory authorities. DDTs with demonstrated predictive accuracy for clinical and microbiological outcomes are needed to support decision making. Regulatory endorsement of these DDTs is critical for drug developers, as it promotes confidence in their use in Investigational New Drug and New Drug Application filings. The in vitro hollow fiber system model of tuberculosis (HFS-TB) is able to recapitulate concentration-time profiles (exposure) observed in patients for single drugs and combinations, by evaluating exposure measures for the ability to kill tuberculosis in different physiologic conditions. Monte Carlo simulations make this quantitative output useful to inform susceptibility breakpoints, dosage, and optimal combination regimens in patients, and to design nonclinical experiments in animal models. The Pre-Clinical and Clinical Sciences Working Group within CPTR executed an evidence-based evaluation of the HFS-TB for predictive accuracy. This extensive effort was enabled through the collaboration of subject matter experts representing the pharmaceutical industry, academia, product development partnerships, and regulatory authorities including the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). A comprehensive analysis plan following the regulatory guidance documents for DDT qualification was developed, followed by individual discussions with the FDA and the EMA. The results from the quantitative analyses were submitted to both agencies, pursuing regulatory DDT endorsement. The EMA Qualification Opinion for the HFS-TB DDT was published 26 January 2015 (available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000319.jsp). © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Development of a rational scale to assess the harm of drugs of potential misuse.

PubMed

Nutt, David; King, Leslie A; Saulsbury, William; Blakemore, Colin

2007-03-24

Drug misuse and abuse are major health problems. Harmful drugs are regulated according to classification systems that purport to relate to the harms and risks of each drug. However, the methodology and processes underlying classification systems are generally neither specified nor transparent, which reduces confidence in their accuracy and undermines health education messages. We developed and explored the feasibility of the use of a nine-category matrix of harm, with an expert delphic procedure, to assess the harms of a range of illicit drugs in an evidence-based fashion. We also included five legal drugs of misuse (alcohol, khat, solvents, alkyl nitrites, and tobacco) and one that has since been classified (ketamine) for reference. The process proved practicable, and yielded roughly similar scores and rankings of drug harm when used by two separate groups of experts. The ranking of drugs produced by our assessment of harm differed from those used by current regulatory systems. Our methodology offers a systematic framework and process that could be used by national and international regulatory bodies to assess the harm of current and future drugs of abuse.

Global regulatory developments for clinical stem cell research: diversification and challenges to collaborations.

PubMed

Rosemann, Achim; Bortz, Gabriela; Vasen, Federico; Sleeboom-Faulkner, Margaret

2016-10-01

In this article, we explore regulatory developments in stem cell medicine in seven jurisdictions: Japan, China, India, Argentina, Brazil, the USA and the EU. We will show that the research methods, ethical standards and approval procedures for the market use of clinical stem cell interventions are undergoing an important process of global diversification. We will discuss the implications of this process for international harmonization and the conduct of multicountry clinical research collaborations. It will become clear that the increasing heterogeneity of research standards and regulations in the stem cell field presents a significant challenge to international clinical trial partnerships, especially with countries that diverge from the regulatory models that have been developed in the USA and the EU.

State trends in ecological risk assessment and standard setting

DOE Office of Scientific and Technical Information (OSTI.GOV)

Siegel, M R; Fowler, K M; Bilyard, G R

1993-02-01

The purposes of this paper are (1) to identify key states' activities and plans related to setting cleanup standards using the ecological risk assessment process, and (2) to discuss the impacts these actions may have on the US Department of Energy's (DOE's) environmental restoration program. This report is prepared as part of a larger task, the purpose of which is to identify and assess state regulatory trends and legal developments that may impact DOE's environmental restoration program. Results of this task are intended to provide DOE with advance notice of potentially significant regulatory developments so as to enhance DOE's abilitymore » to influence these developments and to incorporate possible regulatory and policy changes into its planning process.« less

How does mindfulness modulate self-regulation in pre-adolescent children? An integrative neurocognitive review.

PubMed

Kaunhoven, Rebekah Jane; Dorjee, Dusana

2017-03-01

Pre-adolescence is a key developmental period in which complex intrinsic volitional methods of self-regulation are acquired as a result of rapid maturation within the brain networks underlying the self-regulatory processes of attention control and emotion regulation. Fostering adaptive self-regulation skills during this stage of development has strong implications for physical health, emotional and socio-economic outcomes during adulthood. There is a growing interest in mindfulness-based programmes for pre-adolescents with initial findings suggesting self-regulation improvements, however, neurodevelopmental studies on mindfulness with pre-adolescents are scarce. This analytical review outlines an integrative neuro-developmental approach, which combines self-report and behavioural assessments with event related brain potentials (ERPs) to provide a systemic multilevel understanding of the neurocognitive mechanisms of mindfulness in pre-adolescence. We specifically focus on the N2, error related negativity (ERN), error positivity (Pe), P3a, P3b and late positive potential (LPP) ERP components as indexes of mindfulness related modulations in non-volitional bottom-up self-regulatory processes (salience detection, stimulus driven orienting and mind wandering) and volitional top-down self-regulatory processes (endogenous orienting and executive attention). Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Select Biosolids Regulatory Processes

EPA Pesticide Factsheets

Historical Regulatory Development and activities EPA has undertaken to respond to statutory obligations, respond to the National Academy of Sciences, understand pollutants that may occur in sewage sludge, and address dioxins in sewage sludge.

Regulatory immune cells and functions in autoimmunity and transplantation immunology.

PubMed

Papp, Gabor; Boros, Peter; Nakken, Britt; Szodoray, Peter; Zeher, Margit

2017-05-01

In physiological circumstances, various tolerogenic mechanisms support the protection of self-structures during immune responses. However, quantitative and/or qualitative changes in regulatory immune cells and mediators can evoke auto-reactive immune responses, and upon susceptible genetic background, along with the presence of other concomitant etiological factors, autoimmune disease may develop. In transplant immunology, tolerogenic mechanisms are also critical, since the balance between of alloantigen-reactive effector cells and the regulatory immune cells will ultimately determine whether a graft is accepted or rejected. Better understanding of the immunological tolerance and the potential modulations of immune regulatory processes are crucial for developing effective therapies in autoimmune diseases as well as in organ transplantation. In this review, we focus on the novel insights regarding the impaired immune regulation and other relevant factors contributing to the development of auto-reactive and graft-reactive immune responses in autoimmune diseases and transplant rejection, respectively. We also address some promising approaches for modification of immune-regulatory processes and tolerogenic mechanisms in autoimmunity and solid organ transplantation, which may be beneficial in future therapeutic strategies. Copyright © 2017 Elsevier B.V. All rights reserved.

Regulatory Perspectives on Continuous Pharmaceutical Manufacturing: Moving From Theory to Practice: September 26-27, 2016, International Symposium on the Continuous Manufacturing of Pharmaceuticals.

PubMed

Nasr, Moheb M; Krumme, Markus; Matsuda, Yoshihiro; Trout, Bernhardt L; Badman, Clive; Mascia, Salvatore; Cooney, Charles L; Jensen, Keith D; Florence, Alastair; Johnston, Craig; Konstantinov, Konstantin; Lee, Sau L

2017-11-01

Continuous manufacturing plays a key role in enabling the modernization of pharmaceutical manufacturing. The fate of this emerging technology will rely, in large part, on the regulatory implementation of this novel technology. This paper, which is based on the 2nd International Symposium on the Continuous Manufacturing of Pharmaceuticals, describes not only the advances that have taken place since the first International Symposium on Continuous Manufacturing of Pharmaceuticals in 2014, but the regulatory landscape that exists today. Key regulatory concepts including quality risk management, batch definition, control strategy, process monitoring and control, real-time release testing, data processing and management, and process validation/verification are outlined. Support from regulatory agencies, particularly in the form of the harmonization of regulatory expectations, will be crucial to the successful implementation of continuous manufacturing. Collaborative efforts, among academia, industry, and regulatory agencies, are the optimal solution for ensuring a solid future for this promising manufacturing technology. Copyright © 2017 American Pharmacists Association®. All rights reserved.

Identification of miRNA-mRNA regulatory modules by exploring collective group relationships.

PubMed

Masud Karim, S M; Liu, Lin; Le, Thuc Duy; Li, Jiuyong

2016-01-11

microRNAs (miRNAs) play an essential role in the post-transcriptional gene regulation in plants and animals. They regulate a wide range of biological processes by targeting messenger RNAs (mRNAs). Evidence suggests that miRNAs and mRNAs interact collectively in gene regulatory networks. The collective relationships between groups of miRNAs and groups of mRNAs may be more readily interpreted than those between individual miRNAs and mRNAs, and thus are useful for gaining insight into gene regulation and cell functions. Several computational approaches have been developed to discover miRNA-mRNA regulatory modules (MMRMs) with a common aim to elucidate miRNA-mRNA regulatory relationships. However, most existing methods do not consider the collective relationships between a group of miRNAs and the group of targeted mRNAs in the process of discovering MMRMs. Our aim is to develop a framework to discover MMRMs and reveal miRNA-mRNA regulatory relationships from the heterogeneous expression data based on the collective relationships. We propose DIscovering COllective group RElationships (DICORE), an effective computational framework for revealing miRNA-mRNA regulatory relationships. We utilize the notation of collective group relationships to build the computational framework. The method computes the collaboration scores of the miRNAs and mRNAs on the basis of their interactions with mRNAs and miRNAs, respectively. Then it determines the groups of miRNAs and groups of mRNAs separately based on their respective collaboration scores. Next, it calculates the strength of the collective relationship between each pair of miRNA group and mRNA group using canonical correlation analysis, and the group pairs with significant canonical correlations are considered as the MMRMs. We applied this method to three gene expression datasets, and validated the computational discoveries. Analysis of the results demonstrates that a large portion of the regulatory relationships discovered by DICORE is consistent with the experimentally confirmed databases. Furthermore, it is observed that the top mRNAs that are regulated by the miRNAs in the identified MMRMs are highly relevant to the biological conditions of the given datasets. It is also shown that the MMRMs identified by DICORE are more biologically significant and functionally enriched.

Source sampling of particulate matter emissions from cotton harvesting - System field testing and emission factor development

USDA-ARS?s Scientific Manuscript database

Emission factors are used in the air pollution regulatory process to quantify the mass of pollutants emitted from a source. Accurate emission factors must be used in the air pollution regulatory process to ensure fair and appropriate regulation for all sources. Agricultural sources, including cotton...

Accelerating drug development and approval.

PubMed

Cole, Patrick

2010-01-01

Regulatory agencies are the gateway between the pharma/biotech industry and patients and can serve as stimulators of new drug development. This article highlights several means of doing so implemented thus far, many with already impressive histories, such as orphan drug legislation, and others of a more experimental nature, such as the FDA's priority review voucher program. These initiatives represent different approaches to finding treatments for rare and widespread but neglected diseases, as well as speeding the development process for pharmaceutical and biological agents more generally. Commercial incentives, streamlined regulatory processing, exploratory trial designs, research assistance and cash infusions are all means of promoting drug development being explored in the United States, Europe and beyond. In some cases, such as fast track designation and priority review vouchers, regulatory agencies have turned their own processes into incentives, offering advantageous alternative routes to product approval, like a faster lane on the highway for vehicles carrying multiple passengers. In 2009, regulatory agencies and the governments they represent also had to confront two tremendous challenges: the global recession and the H1N1 influenza virus pandemic. These tests have been met with increased funding in the former case and coordinated efforts to develop, approve and stockpile H1N1 vaccines in the latter.

The European Regulatory Environment of RNA-Based Vaccines.

PubMed

Hinz, Thomas; Kallen, Kajo; Britten, Cedrik M; Flamion, Bruno; Granzer, Ulrich; Hoos, Axel; Huber, Christoph; Khleif, Samir; Kreiter, Sebastian; Rammensee, Hans-Georg; Sahin, Ugur; Singh-Jasuja, Harpreet; Türeci, Özlem; Kalinke, Ulrich

2017-01-01

A variety of different mRNA-based drugs are currently in development. This became possible, since major breakthroughs in RNA research during the last decades allowed impressive improvements of translation, stability and delivery of mRNA. This article focuses on antigen-encoding RNA-based vaccines that are either directed against tumors or pathogens. mRNA-encoded vaccines are developed both for preventive or therapeutic purposes. Most mRNA-based vaccines are directly administered to patients. Alternatively, primary autologous cells from cancer patients are modified ex vivo by the use of mRNA and then are adoptively transferred to patients. In the EU no regulatory guidelines presently exist that specifically address mRNA-based vaccines. The existing regulatory framework, however, clearly defines that mRNA-based vaccines in most cases have to be centrally approved. Interestingly, depending on whether RNA-based vaccines are directed against tumors or infectious disease, they are formally considered gene therapy products or not, respectively. Besides an overview on the current clinical use of mRNA vaccines in various therapeutic areas a detailed discussion of the current regulatory situation is provided and regulatory perspectives are discussed.

Qualitatively modelling and analysing genetic regulatory networks: a Petri net approach.

PubMed

Steggles, L Jason; Banks, Richard; Shaw, Oliver; Wipat, Anil

2007-02-01

New developments in post-genomic technology now provide researchers with the data necessary to study regulatory processes in a holistic fashion at multiple levels of biological organization. One of the major challenges for the biologist is to integrate and interpret these vast data resources to gain a greater understanding of the structure and function of the molecular processes that mediate adaptive and cell cycle driven changes in gene expression. In order to achieve this biologists require new tools and techniques to allow pathway related data to be modelled and analysed as network structures, providing valuable insights which can then be validated and investigated in the laboratory. We propose a new technique for constructing and analysing qualitative models of genetic regulatory networks based on the Petri net formalism. We take as our starting point the Boolean network approach of treating genes as binary switches and develop a new Petri net model which uses logic minimization to automate the construction of compact qualitative models. Our approach addresses the shortcomings of Boolean networks by providing access to the wide range of existing Petri net analysis techniques and by using non-determinism to cope with incomplete and inconsistent data. The ideas we present are illustrated by a case study in which the genetic regulatory network controlling sporulation in the bacterium Bacillus subtilis is modelled and analysed. The Petri net model construction tool and the data files for the B. subtilis sporulation case study are available at http://bioinf.ncl.ac.uk/gnapn.

An MRM-based workflow for absolute quantitation of lysine-acetylated metabolic enzymes in mouse liver.

PubMed

Xu, Leilei; Wang, Fang; Xu, Ying; Wang, Yi; Zhang, Cuiping; Qin, Xue; Yu, Hongxiu; Yang, Pengyuan

2015-12-07

As a key post-translational modification mechanism, protein acetylation plays critical roles in regulating and/or coordinating cell metabolism. Acetylation is a prevalent modification process in enzymes. Protein acetylation modification occurs in sub-stoichiometric amounts; therefore extracting biologically meaningful information from these acetylation sites requires an adaptable, sensitive, specific, and robust method for their quantification. In this work, we combine immunoassays and multiple reaction monitoring-mass spectrometry (MRM-MS) technology to develop an absolute quantification for acetylation modification. With this hybrid method, we quantified the acetylation level of metabolic enzymes, which could demonstrate the regulatory mechanisms of the studied enzymes. The development of this quantitative workflow is a pivotal step for advancing our knowledge and understanding of the regulatory effects of protein acetylation in physiology and pathophysiology.

Drug Repurposing from an Academic Perspective.

PubMed

Oprea, Tudor I; Bauman, Julie E; Bologa, Cristian G; Buranda, Tione; Chigaev, Alexandre; Edwards, Bruce S; Jarvik, Jonathan W; Gresham, Hattie D; Haynes, Mark K; Hjelle, Brian; Hromas, Robert; Hudson, Laurie; Mackenzie, Debra A; Muller, Carolyn Y; Reed, John C; Simons, Peter C; Smagley, Yelena; Strouse, Juan; Surviladze, Zurab; Thompson, Todd; Ursu, Oleg; Waller, Anna; Wandinger-Ness, Angela; Winter, Stuart S; Wu, Yang; Young, Susan M; Larson, Richard S; Willman, Cheryl; Sklar, Larry A

2011-01-01

Academia and small business research units are poised to play an increasing role in drug discovery, with drug repurposing as one of the major areas of activity. Here we summarize project status for a number of drugs or classes of drugs: raltegravir, cyclobenzaprine, benzbromarone, mometasone furoate, astemizole, R-naproxen, ketorolac, tolfenamic acid, phenothiazines, methylergonovine maleate and beta-adrenergic receptor drugs, respectively. Based on this multi-year, multi-project experience we discuss strengths and weaknesses of academic-based drug repurposing research. Translational, target and disease foci are strategic advantages fostered by close proximity and frequent interactions between basic and clinical scientists, which often result in discovering new modes of action for approved drugs. On the other hand, lack of integration with pharmaceutical sciences and toxicology, lack of appropriate intellectual coverage and issues related to dosing and safety may lead to significant drawbacks. The development of a more streamlined regulatory process world-wide, and the development of pre-competitive knowledge transfer systems such as a global healthcare database focused on regulatory and scientific information for drugs world-wide, are among the ideas proposed to improve the process of academic drug discovery and repurposing, and to overcome the "valley of death" by bridging basic to clinical sciences.

Drug Repurposing from an Academic Perspective

PubMed Central

Oprea, Tudor I.; Bauman, Julie E.; Bologa, Cristian G.; Buranda, Tione; Chigaev, Alexandre; Edwards, Bruce S.; Jarvik, Jonathan W.; Gresham, Hattie D.; Haynes, Mark K.; Hjelle, Brian; Hromas, Robert; Hudson, Laurie; Mackenzie, Debra A.; Muller, Carolyn Y.; Reed, John C.; Simons, Peter C.; Smagley, Yelena; Strouse, Juan; Surviladze, Zurab; Thompson, Todd; Ursu, Oleg; Waller, Anna; Wandinger-Ness, Angela; Winter, Stuart S.; Wu, Yang; Young, Susan M.; Larson, Richard S.; Willman, Cheryl; Sklar, Larry A.

2011-01-01

Academia and small business research units are poised to play an increasing role in drug discovery, with drug repurposing as one of the major areas of activity. Here we summarize project status for a number of drugs or classes of drugs: raltegravir, cyclobenzaprine, benzbromarone, mometasone furoate, astemizole, R-naproxen, ketorolac, tolfenamic acid, phenothiazines, methylergonovine maleate and beta-adrenergic receptor drugs, respectively. Based on this multi-year, multi-project experience we discuss strengths and weaknesses of academic-based drug repurposing research. Translational, target and disease foci are strategic advantages fostered by close proximity and frequent interactions between basic and clinical scientists, which often result in discovering new modes of action for approved drugs. On the other hand, lack of integration with pharmaceutical sciences and toxicology, lack of appropriate intellectual coverage and issues related to dosing and safety may lead to significant drawbacks. The development of a more streamlined regulatory process world-wide, and the development of pre-competitive knowledge transfer systems such as a global healthcare database focused on regulatory and scientific information for drugs world-wide, are among the ideas proposed to improve the process of academic drug discovery and repurposing, and to overcome the “valley of death” by bridging basic to clinical sciences. PMID:22368688

Design Considerations in Development of a Mobile Health Intervention Program: The TEXT ME and TEXTMEDS Experience

PubMed Central

Thakkar, Jay; Barry, Tony; Thiagalingam, Aravinda; Redfern, Julie; McEwan, Alistair L; Rodgers, Anthony

2016-01-01

Background Mobile health (mHealth) has huge potential to deliver preventative health services. However, there is paucity of literature on theoretical constructs, technical, practical, and regulatory considerations that enable delivery of such services. Objectives The objective of this study was to outline the key considerations in the development of a text message-based mHealth program; thus providing broad recommendations and guidance to future researchers designing similar programs. Methods We describe the key considerations in designing the intervention with respect to functionality, technical infrastructure, data management, software components, regulatory requirements, and operationalization. We also illustrate some of the potential issues and decision points utilizing our experience of developing text message (short message service, SMS) management systems to support 2 large randomized controlled trials: TEXT messages to improve MEDication adherence & Secondary prevention (TEXTMEDS) and Tobacco, EXercise and dieT MEssages (TEXT ME). Results The steps identified in the development process were: (1) background research and development of the text message bank based on scientific evidence and disease-specific guidelines, (2) pilot testing with target audience and incorporating feedback, (3) software-hardware customization to enable delivery of complex personalized programs using prespecified algorithms, and (4) legal and regulatory considerations. Additional considerations in developing text message management systems include: balancing the use of customized versus preexisting software systems, the level of automation versus need for human inputs, monitoring, ensuring data security, interface flexibility, and the ability for upscaling. Conclusions A merging of expertise in clinical and behavioral sciences, health and research data management systems, software engineering, and mobile phone regulatory requirements is essential to develop a platform to deliver and manage support programs to hundreds of participants simultaneously as in TEXT ME and TEXTMEDS trials. This research provides broad principles that may assist other researchers in developing mHealth programs. PMID:27847350

Design Considerations in Development of a Mobile Health Intervention Program: The TEXT ME and TEXTMEDS Experience.

PubMed

Thakkar, Jay; Barry, Tony; Thiagalingam, Aravinda; Redfern, Julie; McEwan, Alistair L; Rodgers, Anthony; Chow, Clara K

2016-11-15

Mobile health (mHealth) has huge potential to deliver preventative health services. However, there is paucity of literature on theoretical constructs, technical, practical, and regulatory considerations that enable delivery of such services. The objective of this study was to outline the key considerations in the development of a text message-based mHealth program; thus providing broad recommendations and guidance to future researchers designing similar programs. We describe the key considerations in designing the intervention with respect to functionality, technical infrastructure, data management, software components, regulatory requirements, and operationalization. We also illustrate some of the potential issues and decision points utilizing our experience of developing text message (short message service, SMS) management systems to support 2 large randomized controlled trials: TEXT messages to improve MEDication adherence & Secondary prevention (TEXTMEDS) and Tobacco, EXercise and dieT MEssages (TEXT ME). The steps identified in the development process were: (1) background research and development of the text message bank based on scientific evidence and disease-specific guidelines, (2) pilot testing with target audience and incorporating feedback, (3) software-hardware customization to enable delivery of complex personalized programs using prespecified algorithms, and (4) legal and regulatory considerations. Additional considerations in developing text message management systems include: balancing the use of customized versus preexisting software systems, the level of automation versus need for human inputs, monitoring, ensuring data security, interface flexibility, and the ability for upscaling. A merging of expertise in clinical and behavioral sciences, health and research data management systems, software engineering, and mobile phone regulatory requirements is essential to develop a platform to deliver and manage support programs to hundreds of participants simultaneously as in TEXT ME and TEXTMEDS trials. This research provides broad principles that may assist other researchers in developing mHealth programs. ©Jay Thakkar, Tony Barry, Aravinda Thiagalingam, Julie Redfern, Alistair L McEwan, Anthony Rodgers, Clara K Chow. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 15.11.2016.

NAFTA Minor Use Joint Reviews

EPA Pesticide Factsheets

EPA and Health Canada Pest Management Regulatory Agency (PMRA) worked together to develop a registration process that will permit a regulatory decision of pesticide uses for the minor use grower communities in both countries simultaneously.

Impact of regulatory assessment on clinical studies in Brazil.

PubMed

Russo, Luis Augusto Tavares; Eliaschewitz, Freddy Goldberg; Harada, Vitor; Trefiglio, Roberta Pereira; Picciotti, Raffaella; Machado, Paula Goulart Pinheiro; Kesselring, Gustavo Luiz Ferreira

2016-01-01

Despite the recent expansion of clinical studies allocated to Brazil, the delay of local regulatory deadlines directly impacts their completion. This article examines the allocation process of clinical studies to Brazil in comparison with other countries, as well as the financial impact of studies not completed due to interruption caused by the delay in the regulatory process. The allocation processes of studies were compared in nine countries with similar stages of economic development and countries in Latin America using the websites http://data.worldbank.org/data-catalog/GDP-rankings-table and http://worldpopulationreview.com and clinicaltrials.gov, comprising 185 countries. The 46 studies sponsored by the pharmaceutical industry underwent an analysis of the regulatory review process. 46 studies sponsored by the industry and submitted in the country between June 2007 and June 2013 were analyzed; 18 (39%) were discontinued due to the delay in obtaining the necessary approvals. For the approved studies, patient recruitment began an average of 11 months after the other countries. It is estimated that 530 Brazilians patients did not have the opportunity to participate in these studies. Financial losses were to the order of 14.6 million dollars for the country, including patient, medication and supplies costs, and expenses. Brazil has enormous potential for the realization of clinical studies. Researchers, associations of disabled people and patients with chronic diseases, sponsors and the authorities must work together to develop an approval process that is efficient, predictable and, most of all, transparent. The current regulatory environment must and can be improved and optimized in order to result in tangible benefits for patients, society and the country's scientific development.

NRC`s proposed rulemaking on the documentation and reporting of low-level radioactive waste shipment manifest information

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lahs, W.R.; Haisfield, M.F.

1991-12-31

Since the 1982 promulgation of regulations for the land disposal of low-level radioactive waste (LLW), requirements have been in place to control transfers of LLW intended for disposal at licensed land disposal facilities. These requirements established a manifest tracking system and defined processes to control transfers of LLW intended for disposal at a land disposal facility. Because the regulations did not specify the format for the LLW shipment manifests, it was not unexpected that the two operators of the three currently operating disposal sites should each have developed their own manifest forms. The forms have many similarities and the collectedmore » information, in many cases, is identical; however, these manifests incorporate unique operator preferences and also reflect the needs of the Agreement State regulatory authority in the States where the disposal sites are located. Since Agreement State regulations must be compatible with, but need not always be identical to, those of the Nuclear Regulatory Commission (NRC), the possibility of a proliferation of different manifest forms containing variations in collected information could be envisioned. If these manifests were also to serve a shipping paper purpose, effective integration of the Department of Transportations` (DOT) requirements would also have to be addressed. This wide diversity in uses of manifest information by Federal and State regulatory authorities, other State or Compact entities, and disposal site operators, suggested a single consolidated approach to develop a uniform manifest format with a baseline information content and to define recordkeeping requirements. The NRC, in 1989, had embarked on a rulemaking activity to establish a base set of manifest information needs for regulatory purposes. In response to requests from State and Regional Compact organizations who are attempting to design, develop and operate LLW disposal facilities, and with the general support of Agreement State regulatory authorities, this original data base rulemaking was expanded to include development of a uniform low-level radioactive waste manifest.« less

Can ICT Reform Public Agencies?

NASA Astrophysics Data System (ADS)

Jansen, Arild; Løvdal, Einar

This study examines the reorganisation of the administration of admission to higher education in Norway, which has also included the development of a nationwide, ICT-based case handling system. This reform process was initiated out of the need to provide politicians with information for control and regulatory purposes, and the reform resulted in a centralised management information system. This system, however, has evolved into a coordinated but also partly locally delegated decision-making instrument which processes most of the applications for admission to higher education in Norway.

Advanced Reactor Technologies - Regulatory Technology Development Plan (RTDP)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moe, Wayne L.

This DOE-NE Advanced Small Modular Reactor (AdvSMR) regulatory technology development plan (RTDP) will link critical DOE nuclear reactor technology development programs to important regulatory and policy-related issues likely to impact a “critical path” for establishing a viable commercial AdvSMR presence in the domestic energy market. Accordingly, the regulatory considerations that are set forth in the AdvSMR RTDP will not be limited to any one particular type or subset of advanced reactor technology(s) but rather broadly consider potential regulatory approaches and the licensing implications that accompany all DOE-sponsored research and technology development activity that deal with commercial non-light water reactors. However,more » it is also important to remember that certain “minimum” levels of design and safety approach knowledge concerning these technology(s) must be defined and available to an extent that supports appropriate pre-licensing regulatory analysis within the RTDP. Final resolution to advanced reactor licensing issues is most often predicated on the detailed design information and specific safety approach as documented in a facility license application and submitted for licensing review. Because the AdvSMR RTDP is focused on identifying and assessing the potential regulatory implications of DOE-sponsored reactor technology research very early in the pre-license application development phase, the information necessary to support a comprehensive regulatory analysis of a new reactor technology, and the resolution of resulting issues, will generally not be available. As such, the regulatory considerations documented in the RTDP should be considered an initial “first step” in the licensing process which will continue until a license is issued to build and operate the said nuclear facility. Because a facility license application relies heavily on the data and information generated by technology development studies, the anticipated regulatory importance of key DOE reactor research initiatives should be assessed early in the technology development process. Quality assurance requirements supportive of later licensing activities must also be attached to important research activities to ensure resulting data is usable in that context. Early regulatory analysis and licensing approach planning thus provides a significant benefit to the formulation of research plans and also enables the planning and development of a compatible AdvSMR licensing framework, should significant modification be required.« less

Advanced Reactor Technology -- Regulatory Technology Development Plan (RTDP)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moe, Wayne Leland

This DOE-NE Advanced Small Modular Reactor (AdvSMR) regulatory technology development plan (RTDP) will link critical DOE nuclear reactor technology development programs to important regulatory and policy-related issues likely to impact a “critical path” for establishing a viable commercial AdvSMR presence in the domestic energy market. Accordingly, the regulatory considerations that are set forth in the AdvSMR RTDP will not be limited to any one particular type or subset of advanced reactor technology(s) but rather broadly consider potential regulatory approaches and the licensing implications that accompany all DOE-sponsored research and technology development activity that deal with commercial non-light water reactors. However,more » it is also important to remember that certain “minimum” levels of design and safety approach knowledge concerning these technology(s) must be defined and available to an extent that supports appropriate pre-licensing regulatory analysis within the RTDP. Final resolution to advanced reactor licensing issues is most often predicated on the detailed design information and specific safety approach as documented in a facility license application and submitted for licensing review. Because the AdvSMR RTDP is focused on identifying and assessing the potential regulatory implications of DOE-sponsored reactor technology research very early in the pre-license application development phase, the information necessary to support a comprehensive regulatory analysis of a new reactor technology, and the resolution of resulting issues, will generally not be available. As such, the regulatory considerations documented in the RTDP should be considered an initial “first step” in the licensing process which will continue until a license is issued to build and operate the said nuclear facility. Because a facility license application relies heavily on the data and information generated by technology development studies, the anticipated regulatory importance of key DOE reactor research initiatives should be assessed early in the technology development process. Quality assurance requirements supportive of later licensing activities must also be attached to important research activities to ensure resulting data is usable in that context. Early regulatory analysis and licensing approach planning thus provides a significant benefit to the formulation of research plans and also enables the planning and development of a compatible AdvSMR licensing framework, should significant modification be required.« less

Diverse patterns of genomic targeting by transcriptional regulators in Drosophila melanogaster.

PubMed

Slattery, Matthew; Ma, Lijia; Spokony, Rebecca F; Arthur, Robert K; Kheradpour, Pouya; Kundaje, Anshul; Nègre, Nicolas; Crofts, Alex; Ptashkin, Ryan; Zieba, Jennifer; Ostapenko, Alexander; Suchy, Sarah; Victorsen, Alec; Jameel, Nader; Grundstad, A Jason; Gao, Wenxuan; Moran, Jennifer R; Rehm, E Jay; Grossman, Robert L; Kellis, Manolis; White, Kevin P

2014-07-01

Annotation of regulatory elements and identification of the transcription-related factors (TRFs) targeting these elements are key steps in understanding how cells interpret their genetic blueprint and their environment during development, and how that process goes awry in the case of disease. One goal of the modENCODE (model organism ENCyclopedia of DNA Elements) Project is to survey a diverse sampling of TRFs, both DNA-binding and non-DNA-binding factors, to provide a framework for the subsequent study of the mechanisms by which transcriptional regulators target the genome. Here we provide an updated map of the Drosophila melanogaster regulatory genome based on the location of 84 TRFs at various stages of development. This regulatory map reveals a variety of genomic targeting patterns, including factors with strong preferences toward proximal promoter binding, factors that target intergenic and intronic DNA, and factors with distinct chromatin state preferences. The data also highlight the stringency of the Polycomb regulatory network, and show association of the Trithorax-like (Trl) protein with hotspots of DNA binding throughout development. Furthermore, the data identify more than 5800 instances in which TRFs target DNA regions with demonstrated enhancer activity. Regions of high TRF co-occupancy are more likely to be associated with open enhancers used across cell types, while lower TRF occupancy regions are associated with complex enhancers that are also regulated at the epigenetic level. Together these data serve as a resource for the research community in the continued effort to dissect transcriptional regulatory mechanisms directing Drosophila development. © 2014 Slattery et al.; Published by Cold Spring Harbor Laboratory Press.

Duke Surgery Research Central: an open-source Web application for the improvement of compliance with research regulation.

PubMed

Pietrobon, Ricardo; Shah, Anand; Kuo, Paul; Harker, Matthew; McCready, Mariana; Butler, Christeen; Martins, Henrique; Moorman, C T; Jacobs, Danny O

2006-07-27

Although regulatory compliance in academic research is enforced by law to ensure high quality and safety to participants, its implementation is frequently hindered by cost and logistical barriers. In order to decrease these barriers, we have developed a Web-based application, Duke Surgery Research Central (DSRC), to monitor and streamline the regulatory research process. The main objective of DSRC is to streamline regulatory research processes. The application was built using a combination of paper prototyping for system requirements and Java as the primary language for the application, in conjunction with the Model-View-Controller design model. The researcher interface was designed for simplicity so that it could be used by individuals with different computer literacy levels. Analogously, the administrator interface was designed with functionality as its primary goal. DSRC facilitates the exchange of regulatory documents between researchers and research administrators, allowing for tasks to be tracked and documents to be stored in a Web environment accessible from an Intranet. Usability was evaluated using formal usability tests and field observations. Formal usability results demonstrated that DSRC presented good speed, was easy to learn and use, had a functionality that was easily understandable, and a navigation that was intuitive. Additional features implemented upon request by initial users included: extensive variable categorization (in contrast with data capture using free text), searching capabilities to improve how research administrators could search an extensive number of researcher names, warning messages before critical tasks were performed (such as deleting a task), and confirmatory e-mails for critical tasks (such as completing a regulatory task). The current version of DSRC was shown to have excellent overall usability properties in handling research regulatory issues. It is hoped that its release as an open-source application will promote improved and streamlined regulatory processes for individual academic centers as well as larger research networks.

Duke Surgery Research Central: an open-source Web application for the improvement of compliance with research regulation

PubMed Central

Pietrobon, Ricardo; Shah, Anand; Kuo, Paul; Harker, Matthew; McCready, Mariana; Butler, Christeen; Martins, Henrique; Moorman, CT; Jacobs, Danny O

2006-01-01

Background Although regulatory compliance in academic research is enforced by law to ensure high quality and safety to participants, its implementation is frequently hindered by cost and logistical barriers. In order to decrease these barriers, we have developed a Web-based application, Duke Surgery Research Central (DSRC), to monitor and streamline the regulatory research process. Results The main objective of DSRC is to streamline regulatory research processes. The application was built using a combination of paper prototyping for system requirements and Java as the primary language for the application, in conjunction with the Model-View-Controller design model. The researcher interface was designed for simplicity so that it could be used by individuals with different computer literacy levels. Analogously, the administrator interface was designed with functionality as its primary goal. DSRC facilitates the exchange of regulatory documents between researchers and research administrators, allowing for tasks to be tracked and documents to be stored in a Web environment accessible from an Intranet. Usability was evaluated using formal usability tests and field observations. Formal usability results demonstrated that DSRC presented good speed, was easy to learn and use, had a functionality that was easily understandable, and a navigation that was intuitive. Additional features implemented upon request by initial users included: extensive variable categorization (in contrast with data capture using free text), searching capabilities to improve how research administrators could search an extensive number of researcher names, warning messages before critical tasks were performed (such as deleting a task), and confirmatory e-mails for critical tasks (such as completing a regulatory task). Conclusion The current version of DSRC was shown to have excellent overall usability properties in handling research regulatory issues. It is hoped that its release as an open-source application will promote improved and streamlined regulatory processes for individual academic centers as well as larger research networks. PMID:16872540

The integration of the risk management process with the lifecycle of medical device software.

PubMed

Pecoraro, F; Luzi, D

2014-01-01

The application of software in the Medical Device (MD) domain has become central to the improvement of diagnoses and treatments. The new European regulations that specifically address software as an important component of MD, require complex procedures to make software compliant with safety requirements, introducing thereby new challenges in the qualification and classification of MD software as well as in the performance of risk management activities. Under this perspective, the aim of this paper is to propose an integrated framework that combines the activities to be carried out by the manufacturer to develop safe software within the development lifecycle based on the regulatory requirements reported in US and European regulations as well as in the relevant standards and guidelines. A comparative analysis was carried out to identify the main issues related to the application of the current new regulations. In addition, standards and guidelines recently released to harmonise procedures for the validation of MD software have been used to define the risk management activities to be carried out by the manufacturer during the software development process. This paper highlights the main issues related to the qualification and classification of MD software, providing an analysis of the different regulations applied in Europe and the US. A model that integrates the risk management process within the software development lifecycle has been proposed too. It is based on regulatory requirements and considers software risk analysis as a central input to be managed by the manufacturer already at the initial stages of the software design, in order to prevent MD failures. Relevant changes in the process of MD development have been introduced with the recognition of software being an important component of MDs as stated in regulations and standards. This implies the performance of highly iterative processes that have to integrate the risk management in the framework of software development. It also makes it necessary to involve both medical and software engineering competences to safeguard patient and user safety.

Validation of cell-based fluorescence assays: practice guidelines from the ICSH and ICCS - part IV - postanalytic considerations.

PubMed

Barnett, David; Louzao, Raaul; Gambell, Peter; De, Jitakshi; Oldaker, Teri; Hanson, Curtis A

2013-01-01

Flow cytometry and other technologies of cell-based fluorescence assays are as a matter of good laboratory practice required to validate all assays, which when in clinical practice may pass through regulatory review processes using criteria often defined with a soluble analyte in plasma or serum samples in mind. Recently the U.S. Food and Drug Administration (FDA) has entered into a public dialogue in the U.S. regarding their regulatory interest in laboratory developed tests (LDTs) or so-called home brew assays performed in clinical laboratories. The absence of well-defined guidelines for validation of cell-based assays using fluorescence detection has thus become a subject of concern for the International Council for Standardization of Haematology (ICSH) and International Clinical Cytometry Society (ICCS). Accordingly, a group of over 40 international experts in the areas of test development, test validation, and clinical practice of a variety of assay types using flow cytometry and/or morphologic image analysis were invited to develop a set of practical guidelines useful to in vitro diagnostic (IVD) innovators, clinical laboratories, regulatory scientists, and laboratory inspectors. The focus of the group was restricted to fluorescence reporter reagents, although some common principles are shared by immunohistochemistry or immunocytochemistry techniques and noted where appropriate. The work product of this two year effort is the content of this special issue of this journal, which is published as 5 separate articles, this being Validation of Cell-based Fluorescence Assays: Practice Guidelines from the ICSH and ICCS - Part IV - Postanalytic considerations. © 2013 International Clinical Cytometry Society.

Validation of cell-based fluorescence assays: practice guidelines from the ICSH and ICCS - part II - preanalytical issues.

PubMed

Davis, Bruce H; Dasgupta, Amar; Kussick, Steven; Han, Jin-Yeong; Estrellado, Annalee

2013-01-01

Flow cytometry and other technologies of cell-based fluorescence assays are as a matter of good laboratory practice required to validate all assays, which when in clinical practice may pass through regulatory review processes using criteria often defined with a soluble analyte in plasma or serum samples in mind. Recently the U.S. Food and Drug Administration (FDA) has entered into a public dialogue in the U.S. regarding their regulatory interest in laboratory developed tests (LDTs) or so-called "home brew" assays performed in clinical laboratories. The absence of well-defined guidelines for validation of cell-based assays using fluorescence detection has thus become a subject of concern for the International Council for Standardization of Haematology (ICSH) and International Clinical Cytometry Society (ICCS). Accordingly, a group of over 40 international experts in the areas of test development, test validation, and clinical practice of a variety of assay types using flow cytometry and/or morphologic image analysis were invited to develop a set of practical guidelines useful to in vitro diagnostic (IVD) innovators, clinical laboratories, regulatory scientists, and laboratory inspectors. The focus of the group was restricted to fluorescence reporter reagents, although some common principles are shared by immunohistochemistry or immunocytochemistry techniques and noted where appropriate. The work product of this two year effort is the content of this special issue of this journal, which is published as 5 separate articles, this being Validation of Cell-based Fluorescence Assays: Practice Guidelines from the ICSH and ICCS - Part II - Preanalytical issues. © 2013 International Clinical Cytometry Society. © 2013 International Clinical Cytometry Society.

The role of learning environment on high school chemistry students' motivation and self-regulatory processes

NASA Astrophysics Data System (ADS)

Judd, Jeffrey S.

Changes to the global workforce and technological advancements require graduating high school students to be more autonomous, self-directed, and critical in their thinking. To reflect societal changes, current educational reform has focused on developing more problem-based, collaborative, and student-centered classrooms to promote effective self-regulatory learning strategies, with the goal of helping students adapt to future learning situations and become life-long learners. This study identifies key features that may characterize these "powerful learning environments", which I term "high self-regulating learning environments" for ease of discussion, and examine the environment's role on students' motivation and self-regulatory processes. Using direct observation, surveys, and formal and informal interviews, I identified perceptions, motivations, and self-regulatory strategies of 67 students in my high school chemistry classes as they completed academic tasks in both high and low self-regulating learning environments. With social cognitive theory as a theoretical framework, I then examined how students' beliefs and processes changed after they moved from low to a high self-regulating learning environment. Analyses revealed that key features such as task meaning, utility, complexity, and control appeared to play a role in promoting positive changes in students' motivation and self-regulation. As embedded cases, I also included four students identified as high self-regulating, and four students identified as low self-regulating to examine whether the key features of high and low self-regulating learning environments played a similar role in both groups. Analysis of findings indicates that key features did play a significant role in promoting positive changes in both groups, with high self-regulating students' motivation and self-regulatory strategies generally remaining higher than the low self-regulating students; this was the case in both environments. Findings suggest that classroom learning environments and instruction can be modified using variations of these key features to promote specific or various levels of motivation and self-regulatory skill. In this way, educators may tailor their lessons or design their classrooms to better match and develop students' current level of motivation and self-regulation in order to maximize engagement in an academic task.

Bridging Research and Environmental Regulatory Processes: The Role of Knowledge Brokers

PubMed Central

Pennell, Kelly G.; Thompson, Marcella; Rice, James W.; Senier, Laura; Brown, Phil; Suuberg, Eric

2013-01-01

Federal funding agencies increasingly require research investigators to ensure that federally-sponsored research demonstrates broader societal impact. Specifically, the National Institutes of Environmental Health Sciences (NIEHS) Superfund Research Program (SRP) requires research centers to include research translation and community engagement cores to achieve broader impacts, with special emphasis on improving environmental health policies through better scientific understanding. This paper draws on theoretical insights from the social sciences to show how incorporating knowledge brokers in research centers can facilitate translation of scientific expertise to influence regulatory processes and thus promote public health. Knowledge brokers connect academic researchers with decision-makers, to facilitate the translation of research findings into policies and programs. In this article, we describe the stages of the regulatory process and highlight the role of the knowledge broker and scientific expert at each stage. We illustrate the cooperation of knowledge brokers, scientific experts and policymakers using a case from the Brown University (Brown) SRP. We show how the Brown SRP incorporated knowledge brokers to engage scientific experts with regulatory officials around the emerging public health problem of vapor intrusion. In the Brown SRP, the knowledge broker brought regulatory officials into the research process, to help scientific experts understand the critical nature of this emerging public health threat, and helped scientific experts develop a research agenda that would inform the development of timely measures to protect public health. Our experience shows that knowledge brokers can enhance the impact of environmental research on public health by connecting policy decision-makers with scientific experts at critical points throughout the regulatory process. PMID:24083557

Patient Preferences in Regulatory Benefit-Risk Assessments: A US Perspective.

PubMed

Johnson, F Reed; Zhou, Mo

Demands for greater transparency in US regulatory assessments of benefits and risks, together with growing interest in engaging patients in Food and Drug Administration regulatory decision making, have resulted in several recent regulatory developments. Although Food and Drug Administration's Center for Drug Evaluation and Research (CDER) and Center for Devices and Radiological Health (CDRH) have established patient-engagement initiatives, CDRH has proposed guidelines for considering quantitative data on patients' benefit-risk perspectives, while CDER has focused on a more qualitative approach. We summarize two significant studies that were developed in collaboration and consultation with CDER and CDRH. CDER encouraged a patient advocacy group to propose draft guidance on engaging patient and caregiver stakeholders in regulatory decision making for Duchenne muscular dystrophy. CDRH sponsored a discrete-choice experiment case study to quantify obese respondents' perspectives on "meaningful benefits." CDRH and CDER issued draft guidance in May and June 2015, respectively, on including patient-preference data in regulatory submissions. Both organizations face challenges. CDER is working on integrating qualitative data into existing evidence-based review processes and is exploring options for therapeutic areas not included on a priority list. CDRH has adopted an approach that requires patient-preference data to satisfy standards of valid scientific evidence. Although that strategy could facilitate integrating patient perspectives directly with clinical data on benefits and harms, generating such data requires building capacity. Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

77 FR 50724 - Developing Software Life Cycle Processes for Digital Computer Software Used in Safety Systems of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-22

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0195] Developing Software Life Cycle Processes for Digital... Software Life Cycle Processes for Digital Computer Software used in Safety Systems of Nuclear Power Plants... clarifications, the enhanced consensus practices for developing software life-cycle processes for digital...

Regulatory perspective on remaining challenges for utilization of pharmacogenomics-guided drug developments.

PubMed

Otsubo, Yasuto; Ishiguro, Akihiro; Uyama, Yoshiaki

2013-01-01

Pharmacogenomics-guided drug development has been implemented in practice in the last decade, resulting in increased labeling of drugs with pharmacogenomic information. However, there are still many challenges remaining in utilizing this process. Here, we describe such remaining challenges from the regulatory perspective, specifically focusing on sample collection, biomarker qualification, ethnic factors, codevelopment of companion diagnostics and means to provide drugs for off-target patients. To improve the situation, it is important to strengthen international harmonization and collaboration among academia, industries and regulatory agencies, followed by the establishment of an international guideline on this topic. Communication with a regulatory agency from an early stage of drug development is also a key to success.

Intercellular and systemic spread of RNA and RNAi in plants.

PubMed

Nazim Uddin, Mohammad; Kim, Jae-Yean

2013-01-01

Plants possess dynamic networks of intercellular communication that are crucial for plant development and physiology. In plants, intercellular communication involves a combination of ligand-receptor-based apoplasmic signaling, and plasmodesmata and phloem-mediated symplasmic signaling. The intercellular trafficking of macromolecules, including RNAs and proteins, has emerged as a novel mechanism of intercellular communication in plants. Various forms of regulatory RNAs move over distinct cellular boundaries through plasmodesmata and phloem. This plant-specific, non-cell-autonomous RNA trafficking network is also involved in development, nutrient homeostasis, gene silencing, pathogen defense, and many other physiological processes. However, the mechanism underlying macromolecular trafficking in plants remains poorly understood. Current progress made in RNA trafficking research and its biological relevance to plant development will be summarized. Diverse plant regulatory mechanisms of cell-to-cell and systemic long-distance transport of RNAs, including mRNAs, viral RNAs, and small RNAs, will also be discussed. Copyright © 2013 John Wiley & Sons, Ltd.

An Optimal Free Energy Dissipation Strategy of the MinCDE Oscillator in Regulating Symmetric Bacterial Cell Division

PubMed Central

Xiong, Liping; Lan, Ganhui

2015-01-01

Sustained molecular oscillations are ubiquitous in biology. The obtained oscillatory patterns provide vital functions as timekeepers, pacemakers and spacemarkers. Models based on control theory have been introduced to explain how specific oscillatory behaviors stem from protein interaction feedbacks, whereas the energy dissipation through the oscillating processes and its role in the regulatory function remain unexplored. Here we developed a general framework to assess an oscillator’s regulation performance at different dissipation levels. Using the Escherichia coli MinCDE oscillator as a model system, we showed that a sufficient amount of energy dissipation is needed to switch on the oscillation, which is tightly coupled to the system’s regulatory performance. Once the dissipation level is beyond this threshold, unlike stationary regulators’ monotonic performance-to-cost relation, excess dissipation at certain steps in the oscillating process damages the oscillator’s regulatory performance. We further discovered that the chemical free energy from ATP hydrolysis has to be strategically assigned to the MinE-aided MinD release and the MinD immobilization steps for optimal performance, and a higher energy budget improves the robustness of the oscillator. These results unfold a novel mode by which living systems trade energy for regulatory function. PMID:26317492

The Environmental Protection Agency's Safety Standards for Disposal of Spent Nuclear Fuel: Potential Path Forward in Response to the Report of the Blue Ribbon Commission on America's Nuclear Future - 13388

DOE Office of Scientific and Technical Information (OSTI.GOV)

Forinash, Betsy; Schultheisz, Daniel; Peake, Tom

2013-07-01

Following the decision to withdraw the Yucca Mountain license application, the Department of Energy created a Blue Ribbon Commission (BRC) on America's Nuclear Future, tasked with recommending a national strategy to manage the back end of the nuclear fuel cycle. The BRC issued its final report in January 2012, with recommendations covering transportation, storage and disposal of spent nuclear fuel (SNF); potential reprocessing; and supporting institutional measures. The BRC recommendations on disposal of SNF and high-level waste (HLW) are relevant to the U.S. Environmental Protection Agency (EPA), which shares regulatory responsibility with the Nuclear Regulatory Commission (NRC): EPA issues 'generallymore » applicable' performance standards for disposal repositories, which are then implemented in licensing. For disposal, the BRC endorses developing one or more geological repositories, with siting based on an approach that is adaptive, staged and consent-based. The BRC recommends that EPA and NRC work cooperatively to issue generic disposal standards-applying equally to all sites-early in any siting process. EPA previously issued generic disposal standards that apply to all sites other than Yucca Mountain. However, the BRC concluded that the existing regulations should be revisited and revised. The BRC proposes a number of general principles to guide the development of future regulations. EPA continues to review the BRC report and to assess the implications for Agency action, including potential regulatory issues and considerations if EPA develops new or revised generic disposal standards. This review also involves preparatory activities to define potential process and public engagement approaches. (authors)« less

Hydropower Licensing as a Bridge between Climate Science and Applications: Creating Actionable Science for Regulatory Decisionmaking

NASA Astrophysics Data System (ADS)

Ray, A. J.; Barsugli, J. J.; Walker, S. H.

2016-12-01

The Integrated Licensing Process (ILP) of the US Federal Energy Regulatory Commission (FERC) is an example of an existing regulatory process that has the capacity to bridge the gap between science and decision making by clearly delineating existing science, the climate-regulatory nexus, and additional scientific work needed to inform licensing or relicensing of non-federal hydropower projects. In a parallel, but interacting set of legal and regulatory processes, NOAA's National Marine Fisheries Service (NMFS) must conduct analyses based on the best available science in order to implement the requirements of the Endangered Species Act (ESA), the Magnuson-Stevens Act, and NEPA, and to develop terms and conditions to protect fisheries for the 30-50 year term of the license and the longer life of the project itself. Therefore, NMFS must understand the combined effects of hydropower projects and climate change to fulfill its own mandates to protect anadromous fish, protected species and habitat. Federal Executive Order (EO) #13693 on climate change sustainability require use of climate risks in planning, also recommended in NOAA's own guidance on implementing ESA, and the Council on Environmental Quality (CEQ) guidance on implementing NEPA; however, as an independent agency FERC is not subject to that EO. In the past, FERC has consistently rejected NMFS' climate study requests, stating, among other reasons, that climate science is `too uncertain,' and therefore not actionable. Thus, in order for NMFS to get the information needed for its own decision process, NOAA must first persuade FERC that the science is actionable. This presentation will describe our experiences in a multi-year effort by an interdisciplinary team of climate and fishery scientists to develop acceptable climate study requests that address FERC's concerns about uncertainty, for the Susitna-Watana project on Alaska's Susitna River, the LaGrange Project on the Tuolumne R. in California, and the Hiram Project on the Saco R. in Maine. Furthermore, we document that climate studies are needed to meet FERC's own standard that study methodologies be "generally accepted practice" in the community, i.e., that water infrastructure planning and management has evolved to include use of climate risk assessments as best practices.

Drug Development for Pediatric Populations: Regulatory Aspects

PubMed Central

Zisowsky, Jochen; Krause, Andreas; Dingemanse, Jasper

2010-01-01

Pediatric aspects are nowadays integrated early in the development process of a new drug. The stronger enforcement to obtain pediatric information by the regulatory agencies in recent years resulted in an increased number of trials in children. Specific guidelines and requirements from, in particular, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) form the regulatory framework. This review summarizes the regulatory requirements and strategies for pediatric drug development from an industry perspective. It covers pediatric study planning and conduct, considerations for first dose in children, appropriate sampling strategies, and different methods for data generation and analysis to generate knowledge about the pharmacokinetics (PK) and pharmacodynamics (PD) of a drug in children. The role of Modeling and Simulation (M&S) in pediatrics is highlighted—including the regulatory basis—and examples of the use of M&S are illustrated to support pediatric drug development. PMID:27721363

Drug-loaded erythrocytes: on the road toward marketing approval

PubMed Central

Bourgeaux, Vanessa; Lanao, José M; Bax, Bridget E; Godfrin, Yann

2016-01-01

Erythrocyte drug encapsulation is one of the most promising therapeutic alternative approaches for the administration of toxic or rapidly cleared drugs. Drug-loaded erythrocytes can operate through one of the three main mechanisms of action: extension of circulation half-life (bioreactor), slow drug release, or specific organ targeting. Although the clinical development of erythrocyte carriers is confronted with regulatory and development process challenges, industrial development is expanding. The manufacture of this type of product can be either centralized or bedside based, and different procedures are employed for the encapsulation of therapeutic agents. The major challenges for successful industrialization include production scalability, process validation, and quality control of the released therapeutic agents. Advantages and drawbacks of the different manufacturing processes as well as success key points of clinical development are discussed. Several entrapment technologies based on osmotic methods have been industrialized. Companies have already achieved many of the critical clinical stages, thus providing the opportunity in the future to cover a wide range of diseases for which effective therapies are not currently available. PMID:26929599

Drug-loaded erythrocytes: on the road toward marketing approval.

PubMed

Bourgeaux, Vanessa; Lanao, José M; Bax, Bridget E; Godfrin, Yann

2016-01-01

Erythrocyte drug encapsulation is one of the most promising therapeutic alternative approaches for the administration of toxic or rapidly cleared drugs. Drug-loaded erythrocytes can operate through one of the three main mechanisms of action: extension of circulation half-life (bioreactor), slow drug release, or specific organ targeting. Although the clinical development of erythrocyte carriers is confronted with regulatory and development process challenges, industrial development is expanding. The manufacture of this type of product can be either centralized or bedside based, and different procedures are employed for the encapsulation of therapeutic agents. The major challenges for successful industrialization include production scalability, process validation, and quality control of the released therapeutic agents. Advantages and drawbacks of the different manufacturing processes as well as success key points of clinical development are discussed. Several entrapment technologies based on osmotic methods have been industrialized. Companies have already achieved many of the critical clinical stages, thus providing the opportunity in the future to cover a wide range of diseases for which effective therapies are not currently available.

Product-based Safety Certification for Medical Devices Embedded Software.

PubMed

Neto, José Augusto; Figueiredo Damásio, Jemerson; Monthaler, Paul; Morais, Misael

2015-01-01

Worldwide medical device embedded software certification practices are currently focused on manufacturing best practices. In Brazil, the national regulatory agency does not hold a local certification process for software-intensive medical devices and admits international certification (e.g. FDA and CE) from local and international industry to operate in the Brazilian health care market. We present here a product-based certification process as a candidate process to support the Brazilian regulatory agency ANVISA in medical device software regulation. Center of Strategic Technology for Healthcare (NUTES) medical device embedded software certification is based on a solid safety quality model and has been tested with reasonable success against the Class I risk device Generic Infusion Pump (GIP).

75 FR 21723 - Introduction to the Unified Agenda of Federal Regulatory and Deregulatory Actions

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-26

... describing regulatory actions they are developing that may have a significant economic impact on a... local officials early in the process of developing the regulation. In addition, the agency must provide... on the economy of $100 million or more or meets other criteria specified in that Act. The Act...

The roles of patents and research and development incentives in biopharmaceutical innovation.

PubMed

Grabowski, Henry G; DiMasi, Joseph A; Long, Genia

2015-02-01

Patents and other forms of intellectual property protection play essential roles in encouraging innovation in biopharmaceuticals. As part of the "21st Century Cures" initiative, Congress is reviewing the policy mechanisms designed to accelerate the discovery, development, and delivery of new treatments. Debate continues about how best to balance patent and intellectual property incentives to encourage innovation, on the one hand, and generic utilization and price competition, on the other hand. We review the current framework for accomplishing these dual objectives and the important role of patents and regulatory exclusivity (together, the patent-based system), given the lengthy, costly, and risky biopharmaceutical research and development process. We summarize existing targeted incentives, such as for orphan drugs and neglected diseases, and we consider the pros and cons of proposed voluntary or mandatory alternatives to the patent-based system, such as prizes and government research and development contracting. We conclude that patents and regulatory exclusivity provisions are likely to remain the core approach to providing incentives for biopharmaceutical research and development. However, prizes and other voluntary supplements could play a useful role in addressing unmet needs and gaps in specific circumstances. Project HOPE—The People-to-People Health Foundation, Inc.

Preclinical Development of Cell-Based Products: a European Regulatory Science Perspective.

PubMed

McBlane, James W; Phul, Parvinder; Sharpe, Michaela

2018-06-25

This article describes preclinical development of cell-based medicinal products for European markets and discusses European regulatory mechanisms open to developers to aid successful product development. Cell-based medicinal products are diverse, including cells that are autologous or allogeneic, have been genetically modified, or not, or expanded ex vivo, and applied systemically or to an anatomical site different to that of their origin; comments applicable to one product may not be applicable to others, so bespoke development is needed, for all elements - quality, preclinical and clinical. After establishing how the product is produced, proof of potential for therapeutic efficacy, and then safety, of the product need to be determined. This includes understanding biodistribution, persistence and toxicity, including potential for malignant transformation. These elements need to be considered in the context of the intended clinical development. This article describes regulatory mechanisms available to developers to support product development that aim to resolve scientific issues prior to marketing authorization application, to enable patients to have faster access to the product than would otherwise be the case. Developers are encouraged to be aware of both the scientific issues and regulatory mechanisms to ensure patients can be supplied with these products.

Biomedical applications of tissue engineering technology: regulatory issues.

PubMed

Hellman, K B

1995-01-01

Novel emerging technologies such as tissue engineering, which utilize the approaches of molecular and cell biology, biotechnology, as well as materials science and engineering, are being used in the development of a wide range of biomedical products developed by industries regulated by the U.S. Food and Drug Administration (FDA). The FDA's mission is to promote and protect the public health by ensuring the safety and effectiveness of pharmaceuticals and medical devices, including those manufactured by novel technology, as assessed by scientific principles and methods. Regulatory review is conducted on a product-by-product basis. To accomplish its mission over the wide range of products in its regulatory purview, the FDA has six centers, each staffed with the scientific and regulatory expertise to evaluate the products in the center's jurisdiction. Recent legislative and regulatory changes are designed to simplify and facilitate the administrative process for evaluating novel combination products emanating from such interdisciplinary technology as tissue engineering and to resolve questions of product regulatory jurisdiction. Under the new procedures, the FDA may designate a lead FDA center for product review based on the primary mode of action of the combination product, with additional center(s) designated to assist in the evaluation in a collaborative or consultative capacity. In addition, FDA centers have increased their cooperation and information sharing with regard to evolving interdisciplinary technology. The FDA InterCenter Tissue Engineering Initiative was established to develop information on intercenter efforts in the evaluation of tissue engineering applications and to identify areas for further consideration. The FDA InterCenter Tissue Engineering Working Group, comprised of staff from the Center for Biologies Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH), Center for Drug Evaluation and Research (CDER), and Center for Veterinary Medicine (CVM) has developed a Draft Report considering recent developments in tissue engineering and scientific and regulatory issues in the product application areas. The Working Group has identified generic safety and effectiveness issues for consideration by the research and development community in its development of products. The FDA centers are using multiple approaches at their disposal in the evaluation of tissue engineered products including research, data and information monitoring, regulatory guidance, training and education, and cooperation with public and private groups.

Mammalian synthetic biology for studying the cell

PubMed Central

Mathur, Melina; Xiang, Joy S.

2017-01-01

Synthetic biology is advancing the design of genetic devices that enable the study of cellular and molecular biology in mammalian cells. These genetic devices use diverse regulatory mechanisms to both examine cellular processes and achieve precise and dynamic control of cellular phenotype. Synthetic biology tools provide novel functionality to complement the examination of natural cell systems, including engineered molecules with specific activities and model systems that mimic complex regulatory processes. Continued development of quantitative standards and computational tools will expand capacities to probe cellular mechanisms with genetic devices to achieve a more comprehensive understanding of the cell. In this study, we review synthetic biology tools that are being applied to effectively investigate diverse cellular processes, regulatory networks, and multicellular interactions. We also discuss current challenges and future developments in the field that may transform the types of investigation possible in cell biology. PMID:27932576

Reverse-engineering of gene networks for regulating early blood development from single-cell measurements.

PubMed

Wei, Jiangyong; Hu, Xiaohua; Zou, Xiufen; Tian, Tianhai

2017-12-28

Recent advances in omics technologies have raised great opportunities to study large-scale regulatory networks inside the cell. In addition, single-cell experiments have measured the gene and protein activities in a large number of cells under the same experimental conditions. However, a significant challenge in computational biology and bioinformatics is how to derive quantitative information from the single-cell observations and how to develop sophisticated mathematical models to describe the dynamic properties of regulatory networks using the derived quantitative information. This work designs an integrated approach to reverse-engineer gene networks for regulating early blood development based on singel-cell experimental observations. The wanderlust algorithm is initially used to develop the pseudo-trajectory for the activities of a number of genes. Since the gene expression data in the developed pseudo-trajectory show large fluctuations, we then use Gaussian process regression methods to smooth the gene express data in order to obtain pseudo-trajectories with much less fluctuations. The proposed integrated framework consists of both bioinformatics algorithms to reconstruct the regulatory network and mathematical models using differential equations to describe the dynamics of gene expression. The developed approach is applied to study the network regulating early blood cell development. A graphic model is constructed for a regulatory network with forty genes and a dynamic model using differential equations is developed for a network of nine genes. Numerical results suggests that the proposed model is able to match experimental data very well. We also examine the networks with more regulatory relations and numerical results show that more regulations may exist. We test the possibility of auto-regulation but numerical simulations do not support the positive auto-regulation. In addition, robustness is used as an importantly additional criterion to select candidate networks. The research results in this work shows that the developed approach is an efficient and effective method to reverse-engineer gene networks using single-cell experimental observations.

Clinical development of gene therapy needs a tailored approach: a regulatory perspective from the European Union.

PubMed

Narayanan, Gopalan; Cossu, Giulio; Galli, Maria Cristina; Flory, Egbert; Ovelgonne, Hans; Salmikangas, Paula; Schneider, Christian K; Trouvin, Jean-Hugues

2014-03-01

Gene therapy is a rapidly evolving field that needs an integrated approach, as acknowledged in the concept article on the revision of the guideline on gene transfer medicinal products. The first gene therapy application for marketing authorization was approved in the International Conference on Harmonisation (ICH) region in 2012, the product being Alipogene tiparvovec. The regulatory process for this product has been commented on extensively, highlighting the challenges posed by such a novel technology. Here, as current or previous members of the Committee for Advanced Therapies, we share our perspectives and views on gene therapy as a treatment modality based on current common understanding and regulatory experience of gene therapy products in the European Union to date. It is our view that a tailored approach is needed for a given gene therapy product in order to achieve successful marketing authorization.

A future scenario of the global regulatory landscape regarding genome-edited crops

PubMed Central

Araki, Motoko

2017-01-01

ABSTRACT The global agricultural landscape regarding the commercial cultivation of genetically modified (GM) crops is mosaic. Meanwhile, a new plant breeding technique, genome editing is expected to make genetic engineering-mediated crop breeding more socially acceptable because it can be used to develop crop varieties without introducing transgenes, which have hampered the regulatory review and public acceptance of GM crops. The present study revealed that product- and process-based concepts have been implemented to regulate GM crops in 30 countries. Moreover, this study analyzed the regulatory responses to genome-edited crops in the USA, Argentina, Sweden and New Zealand. The findings suggested that countries will likely be divided in their policies on genome-edited crops: Some will deregulate transgene-free crops, while others will regulate all types of crops that have been modified by genome editing. These implications are discussed from the viewpoint of public acceptance. PMID:27960622

Identification of Regulatory DNA Elements Using Genome-wide Mapping of DNase I Hypersensitive Sites during Tomato Fruit Development.

PubMed

Qiu, Zhengkun; Li, Ren; Zhang, Shuaibin; Wang, Ketao; Xu, Meng; Li, Jiayang; Du, Yongchen; Yu, Hong; Cui, Xia

2016-08-01

Development and ripening of tomato fruit are precisely controlled by transcriptional regulation, which depends on the orchestrated accessibility of regulatory proteins to promoters and other cis-regulatory DNA elements. This accessibility and its effect on gene expression play a major role in defining the developmental process. To understand the regulatory mechanism and functional elements modulating morphological and anatomical changes during fruit development, we generated genome-wide high-resolution maps of DNase I hypersensitive sites (DHSs) from the fruit tissues of the tomato cultivar "Moneymaker" at 20 days post anthesis as well as break stage. By exploring variation of DHSs across fruit development stages, we pinpointed the most likely hypersensitive sites related to development-specific genes. By detecting binding motifs on DHSs of these development-specific genes or genes in the ascorbic acid biosynthetic pathway, we revealed the common regulatory elements contributing to coordinating gene transcription of plant ripening and specialized metabolic pathways. Our results contribute to a better understanding of the regulatory dynamics of genes involved in tomato fruit development and ripening. Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.

From molecule to market access: drug regulatory science as an upcoming discipline.

PubMed

Gispen-de Wied, Christine C; Leufkens, Hubertus G M

2013-11-05

Regulatory science as a discipline has evolved over the past years with the object to boost and promote scientific rationale behind benefit/risk and decision making by regulatory authorities. The European Medicines Agency, EMA, the Food and Drug Administration, FDA, and the Japanese Pharmaceutical and Medical Devices Agency, PMDA, highlighted in their distinct ways the importance of regulatory science as a basis of good quality assessment in their strategic plans. The Medicines Evaluation Board, MEB, states: 'regulatory science is the science of developing and validating new standards and tools to evaluate and assess the benefit/risk of medicinal products, facilitating sound and transparent regulatory decision making'. Through analysis of regulatory frameworks itself and their effectiveness, however, regulatory science can also advance knowledge of these systems in general. The comprehensive guidance that is issued to complete an application dossier for regulatory product approval has seldomly been scrutinized for its efficiency. Since it is the task of regulatory authorities to protect and promote public health, it is understood that they take a cautious approach in regulating drugs prior to market access. In general, the authorities are among the first to be blamed if dangerous or useless drugs were allowed to the market. Yet, building a regulatory framework that is not challenged continuously in terms of deliverables for public health and cost-effectiveness, might be counterproductive in the end. Regulatory science and research can help understand how and why regulatory decisions are made, and where renewed discussions may be warranted. The MEB supports regulatory science as an R&D activity to fuel primary regulatory processes on product evaluation and vigilance, but also invests in a 'looking into the mirror' approach. Along the line of the drug life-cycle, publicly available data are reviewed and their regulatory impact highlighted. If made explicit, regulatory research can open the door to evidence based regulatory practice and serve the regulator's contribution to innovative drug licensing today. Copyright © 2013 Elsevier B.V. All rights reserved.

Dynamic integration of splicing within gene regulatory pathways

PubMed Central

Braunschweig, Ulrich; Gueroussov, Serge; Plocik, Alex; Graveley, Brenton R.; Blencowe, Benjamin J.

2013-01-01

Precursor mRNA splicing is one of the most highly regulated processes in metazoan species. In addition to generating vast repertoires of RNAs and proteins, splicing has a profound impact on other gene regulatory layers, including mRNA transcription, turnover, transport and translation. Conversely, factors regulating chromatin and transcription complexes impact the splicing process. This extensive cross-talk between gene regulatory layers takes advantage of dynamic spatial, physical and temporal organizational properties of the cell nucleus, and further emphasizes the importance of developing a multidimensional understanding of splicing control. PMID:23498935

Assuring the quality, safety, and efficacy of DNA vaccines.

PubMed

Robertson, J S; Griffiths, E

2001-02-01

Scientists in academia whose research is aimed at the development of a novel vaccine or approach to vaccination may not always be fully aware of the regulatory process by which a candidate vaccine becomes a licensed product. It is useful for such scientists to be aware of these processes as the development of a novel vaccine could be problematic owing to the starting material often being developed in a research laboratory under ill-defined conditions. This paper examines the regulatory process with respect to the development of a DNA vaccine. DNA vaccines present unusual safety considerations that must be addressed during preclinical safety studies, including adverse immunopathology, genotoxicity through integration into a vaccinees chromosomes, and the potential for the formation of anti-DNA antibodies.

Assuring the quality, safety, and efficacy of DNA vaccines.

PubMed

Robertson, James S; Griffiths, Elwyn

2006-01-01

Scientists in academia whose research is aimed at the development of a novel vaccine or approach to vaccination may not always be fully aware of the regulatory process by which a candidate vaccine becomes a licensed product. It is useful for such scientists to be aware of these processes, as the development of a novel vaccine could be problematic as a result of the starting material often being developed in a research laboratory under ill-defined conditions. This chapter examines the regulatory process with respect to the development of a DNA vaccine. DNA vaccines present unusual safety considerations which must be addressed during nonclinical safety studies, including adverse immunopathology, genotoxicity through integration into a vaccinee's chromosomes and the potential for the formation of anti-DNA antibodies.

Comparative analysis of gene regulatory networks: from network reconstruction to evolution.

PubMed

Thompson, Dawn; Regev, Aviv; Roy, Sushmita

2015-01-01

Regulation of gene expression is central to many biological processes. Although reconstruction of regulatory circuits from genomic data alone is therefore desirable, this remains a major computational challenge. Comparative approaches that examine the conservation and divergence of circuits and their components across strains and species can help reconstruct circuits as well as provide insights into the evolution of gene regulatory processes and their adaptive contribution. In recent years, advances in genomic and computational tools have led to a wealth of methods for such analysis at the sequence, expression, pathway, module, and entire network level. Here, we review computational methods developed to study transcriptional regulatory networks using comparative genomics, from sequence to functional data. We highlight how these methods use evolutionary conservation and divergence to reliably detect regulatory components as well as estimate the extent and rate of divergence. Finally, we discuss the promise and open challenges in linking regulatory divergence to phenotypic divergence and adaptation.

Can We Fix This? Parent-Child Repair Processes and Preschoolers' Regulatory Skills.

PubMed

Kemp, Christine J; Lunkenheimer, Erika; Albrecht, Erin C; Chen, Deborah

2016-10-01

The repair of difficult parent-child interactions is a marker of healthy functioning in infancy, but less is known about repair processes during early childhood. We used dynamic systems methods to investigate dyadic repair in mothers and their 3-year-old children ( N = 96) and its prediction of children's emotion regulation and behavior problems at a four-month follow-up. Mothers and children completed free play and challenging puzzle tasks. Repair was operationalized as the conditional probability of moving into a dyadic adaptive behavior region after individual or dyadic maladaptive behavior (e.g., child noncompliance, parental criticism). Overall, dyads repaired approximately half their maladaptive behaviors. A greater likelihood of repair during the puzzle task predicted better child emotion regulation and fewer behavior problems in preschool. Results suggest dyadic repair is an important process in early childhood and provide further evidence for the connection between parent-child coregulation and children's developing regulatory capacities. Implications for family-based interventions are discussed.

Screening Methodologies to Support Risk and Technology ...

EPA Pesticide Factsheets

The Clean Air Act establishes a two-stage regulatory process for addressing emissions of hazardous air pollutants (HAPs) from stationary sources. In the first stage, the Act requires the EPA to develop technology-based standards for categories of industrial sources. We have largely completed the required “Maximum Achievable Control Technology” (MACT) standards. In the second stage of the regulatory process, EPA must review each MACT standard at least every eight years and revise them as necessary, “taking into account developments in practices, processes and control technologies.” We call this requirement the “technology review.” EPA is also required to complete a one-time assessment of the health and environmental risks that remain after sources come into compliance with MACT. This residual risk review also must be done within 8 years of setting the initial MACT standard. If additional risk reductions are necessary to protect public health with an ample margin of safety or to prevent adverse environmental effects, EPA must develop standards to address these remaining risks. Because the risk review is an important component of the RTR process, EPA is seeking SAB input on the scientific credibility of specific enhancements made to our risk assessment methodologies, particularly with respect to screening methodologies, since the last SAB review was completed in 2010. These enhancements to our risk methodologies are outlined in the document title

Assessment Methodology for Process Validation Lifecycle Stage 3A.

PubMed

Sayeed-Desta, Naheed; Pazhayattil, Ajay Babu; Collins, Jordan; Chen, Shu; Ingram, Marzena; Spes, Jana

2017-07-01

The paper introduces evaluation methodologies and associated statistical approaches for process validation lifecycle Stage 3A. The assessment tools proposed can be applied to newly developed and launched small molecule as well as bio-pharma products, where substantial process and product knowledge has been gathered. The following elements may be included in Stage 3A: number of 3A batch determination; evaluation of critical material attributes, critical process parameters, critical quality attributes; in vivo in vitro correlation; estimation of inherent process variability (IPV) and PaCS index; process capability and quality dashboard (PCQd); and enhanced control strategy. US FDA guidance on Process Validation: General Principles and Practices, January 2011 encourages applying previous credible experience with suitably similar products and processes. A complete Stage 3A evaluation is a valuable resource for product development and future risk mitigation of similar products and processes. Elements of 3A assessment were developed to address industry and regulatory guidance requirements. The conclusions made provide sufficient information to make a scientific and risk-based decision on product robustness.

Gene and Metabolite Regulatory Network Analysis of Early Developing Fruit Tissues Highlights New Candidate Genes for the Control of Tomato Fruit Composition and Development1[C][W][OA

PubMed Central

Mounet, Fabien; Moing, Annick; Garcia, Virginie; Petit, Johann; Maucourt, Michael; Deborde, Catherine; Bernillon, Stéphane; Le Gall, Gwénaëlle; Colquhoun, Ian; Defernez, Marianne; Giraudel, Jean-Luc; Rolin, Dominique; Rothan, Christophe; Lemaire-Chamley, Martine

2009-01-01

Variations in early fruit development and composition may have major impacts on the taste and the overall quality of ripe tomato (Solanum lycopersicum) fruit. To get insights into the networks involved in these coordinated processes and to identify key regulatory genes, we explored the transcriptional and metabolic changes in expanding tomato fruit tissues using multivariate analysis and gene-metabolite correlation networks. To this end, we demonstrated and took advantage of the existence of clear structural and compositional differences between expanding mesocarp and locular tissue during fruit development (12–35 d postanthesis). Transcriptome and metabolome analyses were carried out with tomato microarrays and analytical methods including proton nuclear magnetic resonance and liquid chromatography-mass spectrometry, respectively. Pairwise comparisons of metabolite contents and gene expression profiles detected up to 37 direct gene-metabolite correlations involving regulatory genes (e.g. the correlations between glutamine, bZIP, and MYB transcription factors). Correlation network analyses revealed the existence of major hub genes correlated with 10 or more regulatory transcripts and embedded in a large regulatory network. This approach proved to be a valuable strategy for identifying specific subsets of genes implicated in key processes of fruit development and metabolism, which are therefore potential targets for genetic improvement of tomato fruit quality. PMID:19144766

The impact of transposable elements on mammalian development

PubMed Central

Garcia-Perez, Jose L.; Widmann, Thomas J.; Adams, Ian R.

2018-01-01

Summary Despite often being classified as selfish or junk DNA, transposable elements (TEs) are a group of abundant genetic sequences that significantly impact on mammalian development and genome regulation. In recent years, our understanding of how pre-existing TEs affect genome architecture, gene regulatory networks and protein function during mammalian embryogenesis has dramatically expanded. In addition, the mobilization of active TEs in selected cell types has been shown to generate genetic variation during development and in fully differentiated tissues. Importantly, the ongoing domestication and evolution of TEs appears to provide a rich source of regulatory elements, functional modules and genetic variation that fuels the evolution of mammalian developmental processes. Here, we review the functional impact that TEs exert on mammalian developmental processes and how the somatic activity of TEs can influence gene regulatory networks. PMID:27875251

Emergent adaptive behaviour of GRN-controlled simulated robots in a changing environment.

PubMed

Yao, Yao; Storme, Veronique; Marchal, Kathleen; Van de Peer, Yves

2016-01-01

We developed a bio-inspired robot controller combining an artificial genome with an agent-based control system. The genome encodes a gene regulatory network (GRN) that is switched on by environmental cues and, following the rules of transcriptional regulation, provides output signals to actuators. Whereas the genome represents the full encoding of the transcriptional network, the agent-based system mimics the active regulatory network and signal transduction system also present in naturally occurring biological systems. Using such a design that separates the static from the conditionally active part of the gene regulatory network contributes to a better general adaptive behaviour. Here, we have explored the potential of our platform with respect to the evolution of adaptive behaviour, such as preying when food becomes scarce, in a complex and changing environment and show through simulations of swarm robots in an A-life environment that evolution of collective behaviour likely can be attributed to bio-inspired evolutionary processes acting at different levels, from the gene and the genome to the individual robot and robot population.

Emergent adaptive behaviour of GRN-controlled simulated robots in a changing environment

PubMed Central

Yao, Yao; Storme, Veronique; Marchal, Kathleen

2016-01-01

We developed a bio-inspired robot controller combining an artificial genome with an agent-based control system. The genome encodes a gene regulatory network (GRN) that is switched on by environmental cues and, following the rules of transcriptional regulation, provides output signals to actuators. Whereas the genome represents the full encoding of the transcriptional network, the agent-based system mimics the active regulatory network and signal transduction system also present in naturally occurring biological systems. Using such a design that separates the static from the conditionally active part of the gene regulatory network contributes to a better general adaptive behaviour. Here, we have explored the potential of our platform with respect to the evolution of adaptive behaviour, such as preying when food becomes scarce, in a complex and changing environment and show through simulations of swarm robots in an A-life environment that evolution of collective behaviour likely can be attributed to bio-inspired evolutionary processes acting at different levels, from the gene and the genome to the individual robot and robot population. PMID:28028477

Regulatory Impact Analysis: Amendments to the National Emission Standards for Hazardous Air Pollutants (NESHAP) and New Source Perofrmance Standards (NSPS) for the Portland Cement Manufacturing Industry Final Report

EPA Pesticide Factsheets

For the regulatory process, EPA is required to develop a regulatory impact analysis (RIA). This August 2010 RIA includes an economic impact analysis (EIA) and a small entity impacts analysis and documents the RIA methods and results for the 2010 rules

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wellman, Dawn M.; Freshley, Mark D.; Truex, Michael J.

Current requirements for site remediation and closure are standards-based and are often overly conservative, costly, and in some cases, technically impractical to achieve. Use of risk-informed alternate endpoints provide a means to achieve remediation goals that are permitted by regulations and are protective of human health and the environment. Alternate endpoints enable establishing a path for cleanup that may include intermediate remedial milestones and transition points and/or regulatory alternatives to standards-based remediation. A framework is presented that is centered around developing and refining conceptual models in conjunction with assessing risks and potential endpoints as part of a system-based assessment thatmore » integrates site data with scientific understanding of processes that control the distribution and transport of contaminants in the subsurface and pathways to receptors. This system based assessment and subsequent implementation of the remediation strategy with appropriate monitoring are targeted at providing a holistic approach to addressing risks to human health and the environment. This holistic approach also enables effective predictive analysis of contaminant behavior to provide defensible criteria and data for making long-term decisions. Developing and implementing an alternate endpoint-based approach for remediation and waste site closure presents a number of challenges and opportunities. Categories of these challenges include scientific and technical, regulatory, institutional, and budget and resource allocation issues. Opportunities exist for developing and implementing systems-based approaches with respect to supportive characterization, monitoring, predictive modeling, and remediation approaches.« less

Regulatory administrative databases in FDA's Center for Biologics Evaluation and Research: convergence toward a unified database.

PubMed

Smith, Jeffrey K

2013-04-01

Regulatory administrative database systems within the Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research (CBER) are essential to supporting its core mission, as a regulatory agency. Such systems are used within FDA to manage information and processes surrounding the processing, review, and tracking of investigational and marketed product submissions. This is an area of increasing interest in the pharmaceutical industry and has been a topic at trade association conferences (Buckley 2012). Such databases in CBER are complex, not for the type or relevance of the data to any particular scientific discipline but because of the variety of regulatory submission types and processes the systems support using the data. Commonalities among different data domains of CBER's regulatory administrative databases are discussed. These commonalities have evolved enough to constitute real database convergence and provide a valuable asset for business process intelligence. Balancing review workload across staff, exploring areas of risk in review capacity, process improvement, and presenting a clear and comprehensive landscape of review obligations are just some of the opportunities of such intelligence. This convergence has been occurring in the presence of usual forces that tend to drive information technology (IT) systems development toward separate stovepipes and data silos. CBER has achieved a significant level of convergence through a gradual process, using a clear goal, agreed upon development practices, and transparency of database objects, rather than through a single, discrete project or IT vendor solution. This approach offers a path forward for FDA systems toward a unified database.

RegNetwork: an integrated database of transcriptional and post-transcriptional regulatory networks in human and mouse

PubMed Central

Liu, Zhi-Ping; Wu, Canglin; Miao, Hongyu; Wu, Hulin

2015-01-01

Transcriptional and post-transcriptional regulation of gene expression is of fundamental importance to numerous biological processes. Nowadays, an increasing amount of gene regulatory relationships have been documented in various databases and literature. However, to more efficiently exploit such knowledge for biomedical research and applications, it is necessary to construct a genome-wide regulatory network database to integrate the information on gene regulatory relationships that are widely scattered in many different places. Therefore, in this work, we build a knowledge-based database, named ‘RegNetwork’, of gene regulatory networks for human and mouse by collecting and integrating the documented regulatory interactions among transcription factors (TFs), microRNAs (miRNAs) and target genes from 25 selected databases. Moreover, we also inferred and incorporated potential regulatory relationships based on transcription factor binding site (TFBS) motifs into RegNetwork. As a result, RegNetwork contains a comprehensive set of experimentally observed or predicted transcriptional and post-transcriptional regulatory relationships, and the database framework is flexibly designed for potential extensions to include gene regulatory networks for other organisms in the future. Based on RegNetwork, we characterized the statistical and topological properties of genome-wide regulatory networks for human and mouse, we also extracted and interpreted simple yet important network motifs that involve the interplays between TF-miRNA and their targets. In summary, RegNetwork provides an integrated resource on the prior information for gene regulatory relationships, and it enables us to further investigate context-specific transcriptional and post-transcriptional regulatory interactions based on domain-specific experimental data. Database URL: http://www.regnetworkweb.org PMID:26424082

The history and regulatory mechanism of the Hippo pathway

PubMed Central

Kim, Wantae; Jho, Eek-hoon

2018-01-01

How the organ size is adjusted to the proper size during development and how organs know that they reach the original size during regeneration remain long-standing questions. Based on studies using multiple model organisms and approaches for over 20 years, a consensus has been established that the Hippo pathway plays crucial roles in controlling organ size and maintaining tissue homeostasis. Given the significance of these processes, the dysregulation of the Hippo pathway has also implicated various diseases, such as tissue degeneration and cancer. By regulating the downstream transcriptional coactivators YAP and TAZ, the Hippo pathway coordinates cell proliferation and apoptosis in response to a variety of signals including cell contact inhibition, polarity, mechanical sensation and soluble factors. Since the core components and their functions of the Hippo pathway are evolutionarily conserved, this pathway serves as a global regulator of organ size control. Therefore, further investigation of the regulatory mechanisms will provide physiological insights to better understand tissue homeostasis. In this review, the historical developments and current understandings of the regulatory mechanism of Hippo signaling pathway are discussed. PMID:29397869

Aflatoxin control--how a regulatory agency managed risk from an unavoidable natural toxicant in food and feed.

PubMed

Park, D L; Stoloff, L

1989-04-01

The control by the Food and Drug Administration (FDA) of aflatoxin, a relatively recently discovered, unavoidable natural contaminant produced by specific molds that invade a number of basic food and feedstuffs, provides an example of the varying forces that affect risk assessment and management by a regulatory Agency. This is the story of how the FDA responded to the initial discovery of a potential carcinogenic hazard to humans in a domestic commodity, to the developing information concerning the nature of the hazard, to the economic and political pressures that are created by the impact of natural forces on regulatory controls, and to the restraints of laws within which the Agency must work. This story covers four periods: the years of discovery and action decisions on the basis of meager knowledge and the fear of cancer; the years of tinkering on paper with the regulatory process, the years of digestion of the accumulating knowledge, and the application of that knowledge to actions forced by natural events; and an audit of the current status of knowledge about the hazard from aflatoxin, and proposals for regulatory control based on that knowledge.

Strengthening the regulatory system through the implementation and use of a quality management system.

PubMed

Eisner, Reinhold; Patel, Rakeshkumar

2017-04-20

Quality management systems (QMS), based on ISO 9001 requirements, are applicable to government service organizations such as Health Canada's Biologics and Genetic Therapies Directorate (BGTD). This communication presents the process that the BGTD followed since the early 2000s to implement a quality management system and describes how the regulatory system was improved as a result of this project. BGTD undertook the implementation of a quality management system based on ISO 9001 and containing aspects of ISO 17025 with the goal of strengthening the regulatory system through improvements in the people, processes, and services of the organization. We discuss the strategy used by BGTD to implement the QMS and the benefits that were realized from the various stages of implementation. The eight quality principals upon which the QMS standards of the ISO 9000 series are based were used by senior management as a framework to guide QMS implementation.

Improving academic leadership and oversight in large industry-sponsored clinical trials: the ARO-CRO model

PubMed Central

Goldenberg, Neil A.; Spyropoulos, Alex C.; Halperin, Jonathan L.; Kessler, Craig M.; Schulman, Sam; Turpie, Alexander G. G.; Skene, Allan M.; Cutler, Neal R.

2011-01-01

Standards for clinical trial design, execution, and publication have increased in recent years. However, the current structure for interaction among the pharmaceutical sponsor funding a drug or device development program, the contract research organization (CRO) that typically assists in executing the trial, regulatory agencies, and academicians, provides inadequate leadership and oversight of the development process. Conventional academic steering committees are not provided with the independent infrastructure by which to verify statistical analyses and conclusions regarding safety and efficacy. We propose an alternative approach centered on partnerships between CROs and university-based academic research organizations (AROs). In this model, the ARO takes responsibility for processes that address journal requirements and regulatory expectations for independent academic oversight (including oversight of Steering Committee and Data and Safety Monitoring Board activities), whereas the CRO provides infrastructure for efficient trial execution, site monitoring, and data management. The ARO engages academic experts throughout the trial process and minimizes conflicts of interest in individual industry relationships via diversification of sponsors, agents, and therapeutic areas. Although numerous models can be entertained, the ARO-CRO model is uniquely structured to meet the demand for greater assurance of integrity in clinical trials and the needs of each stakeholder in the process. PMID:21068436

Reconstructing genome-wide regulatory network of E. coli using transcriptome data and predicted transcription factor activities

PubMed Central

2011-01-01

Background Gene regulatory networks play essential roles in living organisms to control growth, keep internal metabolism running and respond to external environmental changes. Understanding the connections and the activity levels of regulators is important for the research of gene regulatory networks. While relevance score based algorithms that reconstruct gene regulatory networks from transcriptome data can infer genome-wide gene regulatory networks, they are unfortunately prone to false positive results. Transcription factor activities (TFAs) quantitatively reflect the ability of the transcription factor to regulate target genes. However, classic relevance score based gene regulatory network reconstruction algorithms use models do not include the TFA layer, thus missing a key regulatory element. Results This work integrates TFA prediction algorithms with relevance score based network reconstruction algorithms to reconstruct gene regulatory networks with improved accuracy over classic relevance score based algorithms. This method is called Gene expression and Transcription factor activity based Relevance Network (GTRNetwork). Different combinations of TFA prediction algorithms and relevance score functions have been applied to find the most efficient combination. When the integrated GTRNetwork method was applied to E. coli data, the reconstructed genome-wide gene regulatory network predicted 381 new regulatory links. This reconstructed gene regulatory network including the predicted new regulatory links show promising biological significances. Many of the new links are verified by known TF binding site information, and many other links can be verified from the literature and databases such as EcoCyc. The reconstructed gene regulatory network is applied to a recent transcriptome analysis of E. coli during isobutanol stress. In addition to the 16 significantly changed TFAs detected in the original paper, another 7 significantly changed TFAs have been detected by using our reconstructed network. Conclusions The GTRNetwork algorithm introduces the hidden layer TFA into classic relevance score-based gene regulatory network reconstruction processes. Integrating the TFA biological information with regulatory network reconstruction algorithms significantly improves both detection of new links and reduces that rate of false positives. The application of GTRNetwork on E. coli gene transcriptome data gives a set of potential regulatory links with promising biological significance for isobutanol stress and other conditions. PMID:21668997

Mammalian synthetic biology for studying the cell.

PubMed

Mathur, Melina; Xiang, Joy S; Smolke, Christina D

2017-01-02

Synthetic biology is advancing the design of genetic devices that enable the study of cellular and molecular biology in mammalian cells. These genetic devices use diverse regulatory mechanisms to both examine cellular processes and achieve precise and dynamic control of cellular phenotype. Synthetic biology tools provide novel functionality to complement the examination of natural cell systems, including engineered molecules with specific activities and model systems that mimic complex regulatory processes. Continued development of quantitative standards and computational tools will expand capacities to probe cellular mechanisms with genetic devices to achieve a more comprehensive understanding of the cell. In this study, we review synthetic biology tools that are being applied to effectively investigate diverse cellular processes, regulatory networks, and multicellular interactions. We also discuss current challenges and future developments in the field that may transform the types of investigation possible in cell biology. © 2017 Mathur et al.

33 CFR 1.05-10 - Regulatory process overview.

Code of Federal Regulations, 2011 CFR

2011-07-01

... regulation, alternatives considered, and potential cost and benefits, including possible environmental... or for changes to an existing regulation. The need may arise due to statutory changes, or be based on... Federal Register. These may include regulatory evaluations, environmental analyses, requests for comments...

33 CFR 1.05-10 - Regulatory process overview.

Code of Federal Regulations, 2010 CFR

2010-07-01

... regulation, alternatives considered, and potential cost and benefits, including possible environmental... or for changes to an existing regulation. The need may arise due to statutory changes, or be based on... Federal Register. These may include regulatory evaluations, environmental analyses, requests for comments...

Regulatory guidelines for biosimilars in Malaysia.

PubMed

Abas, Arpah

2011-09-01

The biosimilars sector continues to attract huge interest and controversy. Biosimilars are new biopharmaceuticals that are "similar" but not identical to the innovator product. Characteristics of biopharmaceuticals are closely related to the manufacturing process, which implies that the products cannot be exactly duplicated. Minuscule differences in the product's structure and manufacturing process can result in different clinical outcome. This raises concerns over the safety, efficacy and even pharmacovigilance of biosimilars. Thus, biosimilars are unique - they are not a true chemical generic and are regulated via a distinct regulatory framework. This report discusses the features of Malaysian regulatory oversight of biosimilars and experience acquired in the evaluation of some products from various countries. Ensuring regulatory position adequately reflects scientific advancement, expertise/resources is key. The regulatory situation is an evolving process. Various guidance documents are being prepared with the aim of developing a uniform global framework towards assuring the dual goal of lower costs and patient safety while expediting the availability of important biosimilar products. Copyright © 2011. Published by Elsevier Ltd.

Finding gene regulatory network candidates using the gene expression knowledge base.

PubMed

Venkatesan, Aravind; Tripathi, Sushil; Sanz de Galdeano, Alejandro; Blondé, Ward; Lægreid, Astrid; Mironov, Vladimir; Kuiper, Martin

2014-12-10

Network-based approaches for the analysis of large-scale genomics data have become well established. Biological networks provide a knowledge scaffold against which the patterns and dynamics of 'omics' data can be interpreted. The background information required for the construction of such networks is often dispersed across a multitude of knowledge bases in a variety of formats. The seamless integration of this information is one of the main challenges in bioinformatics. The Semantic Web offers powerful technologies for the assembly of integrated knowledge bases that are computationally comprehensible, thereby providing a potentially powerful resource for constructing biological networks and network-based analysis. We have developed the Gene eXpression Knowledge Base (GeXKB), a semantic web technology based resource that contains integrated knowledge about gene expression regulation. To affirm the utility of GeXKB we demonstrate how this resource can be exploited for the identification of candidate regulatory network proteins. We present four use cases that were designed from a biological perspective in order to find candidate members relevant for the gastrin hormone signaling network model. We show how a combination of specific query definitions and additional selection criteria derived from gene expression data and prior knowledge concerning candidate proteins can be used to retrieve a set of proteins that constitute valid candidates for regulatory network extensions. Semantic web technologies provide the means for processing and integrating various heterogeneous information sources. The GeXKB offers biologists such an integrated knowledge resource, allowing them to address complex biological questions pertaining to gene expression. This work illustrates how GeXKB can be used in combination with gene expression results and literature information to identify new potential candidates that may be considered for extending a gene regulatory network.

MicroRNA network changes in the brain stem underlie the development of hypertension.

PubMed

DeCicco, Danielle; Zhu, Haisun; Brureau, Anthony; Schwaber, James S; Vadigepalli, Rajanikanth

2015-09-01

Hypertension is a major chronic disease whose molecular mechanisms remain poorly understood. We compared neuroanatomical patterns of microRNAs in the brain stem of the spontaneous hypertensive rat (SHR) to the Wistar Kyoto rat (WKY, control). We quantified 419 well-annotated microRNAs in the nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM), from SHR and WKY rats, during three main stages of hypertension development. Changes in microRNA expression were stage- and region-dependent, with a majority of SHR vs. WKY differential expression occurring at the hypertension onset stage in NTS versus at the prehypertension stage in RVLM. Our analysis identified 24 microRNAs showing time-dependent differential expression in SHR compared with WKY in at least one brain region. We predicted potential gene regulatory targets corresponding to catecholaminergic processes, neuroinflammation, and neuromodulation using the miRWALK and RNA22 databases, and we tested those bioinformatics predictions using high-throughput quantitative PCR to evaluate correlations of differential expression between the microRNAs and their predicted gene targets. We found a novel regulatory network motif consisting of microRNAs likely downregulating a negative regulator of prohypertensive processes such as angiotensin II signaling and leukotriene-based inflammation. Our results provide new evidence on the dynamics of microRNA expression in the development of hypertension and predictions of microRNA-mediated regulatory networks playing a region-dependent role in potentially altering brain-stem cardiovascular control circuit function leading to the development of hypertension. Copyright © 2015 the American Physiological Society.

Resilience as Regulation of Developmental and Family Processes

PubMed Central

MacPhee, David; Lunkenheimer, Erika; Riggs, Nathaniel

2015-01-01

Resilience can be defined as establishing equilibrium subsequent to disturbances to a system caused by significant adversity. When families experience adversity or transitions, multiple regulatory processes may be involved in establishing equilibrium, including adaptability, regulation of negative affect, and effective problem-solving skills. The authors’ resilience-as-regulation perspective integrates insights about the regulation of individual development with processes that regulate family systems. This middle-range theory of family resilience focuses on regulatory processes across levels that are involved in adaptation: whole-family systems such as routines and sense of coherence; coregulation of dyads involving emotion regulation, structuring, and reciprocal influences between social partners; and individual self-regulation. Insights about resilience-as-regulation are then applied to family-strengthening interventions that are designed to promote adaptation to adversity. Unresolved issues are discussed in relation to resilience-as-regulation in families, in particular how risk exposure is assessed, interrelations among family regulatory mechanisms, and how families scaffold the development of children’s resilience. PMID:26568647

A new chapter in pharmaceutical manufacturing: 3D-printed drug products.

PubMed

Norman, James; Madurawe, Rapti D; Moore, Christine M V; Khan, Mansoor A; Khairuzzaman, Akm

2017-01-01

FDA recently approved a 3D-printed drug product in August 2015, which is indicative of a new chapter for pharmaceutical manufacturing. This review article summarizes progress with 3D printed drug products and discusses process development for solid oral dosage forms. 3D printing is a layer-by-layer process capable of producing 3D drug products from digital designs. Traditional pharmaceutical processes, such as tablet compression, have been used for decades with established regulatory pathways. These processes are well understood, but antiquated in terms of process capability and manufacturing flexibility. 3D printing, as a platform technology, has competitive advantages for complex products, personalized products, and products made on-demand. These advantages create opportunities for improving the safety, efficacy, and accessibility of medicines. Although 3D printing differs from traditional manufacturing processes for solid oral dosage forms, risk-based process development is feasible. This review highlights how product and process understanding can facilitate the development of a control strategy for different 3D printing methods. Overall, the authors believe that the recent approval of a 3D printed drug product will stimulate continual innovation in pharmaceutical manufacturing technology. FDA encourages the development of advanced manufacturing technologies, including 3D-printing, using science- and risk-based approaches. Published by Elsevier B.V.

Genotet: An Interactive Web-based Visual Exploration Framework to Support Validation of Gene Regulatory Networks.

PubMed

Yu, Bowen; Doraiswamy, Harish; Chen, Xi; Miraldi, Emily; Arrieta-Ortiz, Mario Luis; Hafemeister, Christoph; Madar, Aviv; Bonneau, Richard; Silva, Cláudio T

2014-12-01

Elucidation of transcriptional regulatory networks (TRNs) is a fundamental goal in biology, and one of the most important components of TRNs are transcription factors (TFs), proteins that specifically bind to gene promoter and enhancer regions to alter target gene expression patterns. Advances in genomic technologies as well as advances in computational biology have led to multiple large regulatory network models (directed networks) each with a large corpus of supporting data and gene-annotation. There are multiple possible biological motivations for exploring large regulatory network models, including: validating TF-target gene relationships, figuring out co-regulation patterns, and exploring the coordination of cell processes in response to changes in cell state or environment. Here we focus on queries aimed at validating regulatory network models, and on coordinating visualization of primary data and directed weighted gene regulatory networks. The large size of both the network models and the primary data can make such coordinated queries cumbersome with existing tools and, in particular, inhibits the sharing of results between collaborators. In this work, we develop and demonstrate a web-based framework for coordinating visualization and exploration of expression data (RNA-seq, microarray), network models and gene-binding data (ChIP-seq). Using specialized data structures and multiple coordinated views, we design an efficient querying model to support interactive analysis of the data. Finally, we show the effectiveness of our framework through case studies for the mouse immune system (a dataset focused on a subset of key cellular functions) and a model bacteria (a small genome with high data-completeness).

Validation of cell-based fluorescence assays: practice guidelines from the ICSH and ICCS - part I - rationale and aims.

PubMed

Davis, Bruce H; Wood, Brent; Oldaker, Teri; Barnett, David

2013-01-01

Flow cytometry and other technologies of cell-based fluorescence assays are as a matter of good laboratory practice required to validate all assays, which when in clinical practice may pass through regulatory review processes using criteria often defined with a soluble analyte in plasma or serum samples in mind. Recently the U.S. Food and Drug Administration (FDA) has entered into a public dialogue in the U.S. regarding their regulatory interest in laboratory developed tests (LDTs) or so-called "home brew" assays performed in clinical laboratories. The absence of well-defined guidelines for validation of cell-based assays using fluorescence detection has thus become a subject of concern for the International Council for Standardization of Haematology (ICSH) and International Clinical Cytometry Society (ICCS). Accordingly, a group of over 40 international experts in the areas of test development, test validation, and clinical practice of a variety of assay types using flow cytometry and/or morphologic image analysis were invited to develop a set of practical guidelines useful to in vitro diagnostic (IVD) innovators, clinical laboratories, regulatory scientists, and laboratory inspectors. The focus of the group was restricted to fluorescence reporter reagents, although some common principles are shared by immunohistochemistry or immunocytochemistry techniques and noted where appropriate. The work product of this two year effort is the content of this special issue of this journal, which is published as 5 separate articles, this being Validation of Cell-based Fluorescence Assays: Practice Guidelines from the ICSH and ICCS - Part I - Rationale and aims. © 2013 International Clinical Cytometry Society. © 2013 International Clinical Cytometry Society.

MO-AB-201-03: The Alphabet Soup of Regulatory Compliance: Being Prepared for Inspections

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kroger, L.

2015-06-15

The role of the Radiation Safety Officer at a medical facility can be complicated. The complexity of the position is based on the breadth of services provided at the institution and the nature of the radioactive materials license. Medical practices are constantly changing and the use of ionizing radiation continues to rise in this area. Some of the newer medical applications involving radiation have unique regulatory and safety issues that must be addressed. Oversight of the uses of radiation start at the local level (radiation safety officer, radiation safety committee) and are heavily impacted by outside agencies (i.e. Nuclear Regulatorymore » Commission, State Radiologic Health, The Joint Commission (TJC), etc). This session will provide both an overview of regulatory oversight and essential compliance practices as well as practical ways to assess and introduce some of the new applications utilizing radioactive materials into your medical facility. Learning Objectives: Regulatory Compliance and Safety with New Radiotherapies: Spheres and Ra-223 (Lance Phillips) Understand the radioactive materials license amendment process to add new radiotherapies (i.e., SIR-Spheres, Therasphere, Xofigo). Understand the AU approval process for microspheres and Xofigo. Examine the training and handling requirements for new procedures. Understand the process involved with protocol development, SOP in order to define roles and responsibilities. The RSO and The RSC: Challenges and Opportunities (Colin Dimock) Understand how to form an effective Committee. Examine what the Committee does for the Program and the RSO. Understand the importance of Committee engagement. Discuss the balance of the complimentary roles of the RSO and the Committee. The Alphabet Soup of Regulatory Compliance: Being Prepared for Inspections (Linda Kroger) Recognize the various regulatory bodies and organizations with oversight or impact in Nuclear Medicine, Radiology and Radiation Oncology. Examine 10CFR35 requirements as they relate to the everyday practice of Nuclear Medicine and Radiation Oncology. Understand the nature of available guidance documents (e.g., NUREG 1556). Examine the commonalities between TJC and CMS preparedness.« less

Use of transcriptome sequencing to understand the pistillate flowering in hickory (Carya cathayensis Sarg.).

PubMed

Huang, You-Jun; Liu, Li-Li; Huang, Jian-Qin; Wang, Zheng-Jia; Chen, Fang-Fang; Zhang, Qi-Xiang; Zheng, Bing-Song; Chen, Ming

2013-10-10

Different from herbaceous plants, the woody plants undergo a long-period vegetative stage to achieve floral transition. They then turn into seasonal plants, flowering annually. In this study, a preliminary model of gene regulations for seasonal pistillate flowering in hickory (Carya cathayensis) was proposed. The genome-wide dynamic transcriptome was characterized via the joint-approach of RNA sequencing and microarray analysis. Differential transcript abundance analysis uncovered the dynamic transcript abundance patterns of flowering correlated genes and their major functions based on Gene Ontology (GO) analysis. To explore pistillate flowering mechanism in hickory, a comprehensive flowering gene regulatory network based on Arabidopsis thaliana was constructed by additional literature mining. A total of 114 putative flowering or floral genes including 31 with differential transcript abundance were identified in hickory. The locations, functions and dynamic transcript abundances were analyzed in the gene regulatory networks. A genome-wide co-expression network for the putative flowering or floral genes shows three flowering regulatory modules corresponding to response to light abiotic stimulus, cold stress, and reproductive development process, respectively. Totally 27 potential flowering or floral genes were recruited which are meaningful to understand the hickory specific seasonal flowering mechanism better. Flowering event of pistillate flower bud in hickory is triggered by several pathways synchronously including the photoperiod, autonomous, vernalization, gibberellin, and sucrose pathway. Totally 27 potential flowering or floral genes were recruited from the genome-wide co-expression network function module analysis. Moreover, the analysis provides a potential FLC-like gene based vernalization pathway and an 'AC' model for pistillate flower development in hickory. This work provides an available framework for pistillate flower development in hickory, which is significant for insight into regulation of flowering and floral development of woody plants.

Use of transcriptome sequencing to understand the pistillate flowering in hickory (Carya cathayensis Sarg.)

PubMed Central

2013-01-01

Background Different from herbaceous plants, the woody plants undergo a long-period vegetative stage to achieve floral transition. They then turn into seasonal plants, flowering annually. In this study, a preliminary model of gene regulations for seasonal pistillate flowering in hickory (Carya cathayensis) was proposed. The genome-wide dynamic transcriptome was characterized via the joint-approach of RNA sequencing and microarray analysis. Results Differential transcript abundance analysis uncovered the dynamic transcript abundance patterns of flowering correlated genes and their major functions based on Gene Ontology (GO) analysis. To explore pistillate flowering mechanism in hickory, a comprehensive flowering gene regulatory network based on Arabidopsis thaliana was constructed by additional literature mining. A total of 114 putative flowering or floral genes including 31 with differential transcript abundance were identified in hickory. The locations, functions and dynamic transcript abundances were analyzed in the gene regulatory networks. A genome-wide co-expression network for the putative flowering or floral genes shows three flowering regulatory modules corresponding to response to light abiotic stimulus, cold stress, and reproductive development process, respectively. Totally 27 potential flowering or floral genes were recruited which are meaningful to understand the hickory specific seasonal flowering mechanism better. Conclusions Flowering event of pistillate flower bud in hickory is triggered by several pathways synchronously including the photoperiod, autonomous, vernalization, gibberellin, and sucrose pathway. Totally 27 potential flowering or floral genes were recruited from the genome-wide co-expression network function module analysis. Moreover, the analysis provides a potential FLC-like gene based vernalization pathway and an 'AC’ model for pistillate flower development in hickory. This work provides an available framework for pistillate flower development in hickory, which is significant for insight into regulation of flowering and floral development of woody plants. PMID:24106755

Treatment of Depression From a Self-Regulation Perspective: Basic Concepts and Applied Strategies in Self-System Therapy.

PubMed

Strauman, Timothy J; Eddington, Kari M

2017-02-01

Self-regulation models of psychopathology provide a theory-based, empirically supported framework for developing psychotherapeutic interventions that complement and extend current cognitive-behavioral models. However, many clinicians are only minimally familiar with the psychology of self-regulation. The aim of the present manuscript is twofold. First, we provide an overview of self-regulation as a motivational process essential to well-being and introduce two related theories of self-regulation which have been applied to depression. Second, we describe how self-regulatory concepts and processes from those two theories have been translated into psychosocial interventions, focusing specifically on self-system therapy (SST), a brief structured treatment for depression that targets personal goal pursuit. Two randomized controlled trials have shown that SST is superior to cognitive therapy for depressed clients with specific self-regulatory deficits, and both studies found evidence that SST works in part by restoring adaptive self-regulation. Self-regulation-based psychotherapeutic approaches to depression hold significant promise for enhancing treatment efficacy and ultimately may provide an individualizable framework for treatment planning.

The Integration of Cognition and Emotion during Infancy and Early Childhood: Regulatory Processes Associated with the Development of Working Memory

ERIC Educational Resources Information Center

Wolfe, Christy D.; Bell, Martha Ann

2007-01-01

This study was an attempt to integrate cognitive development (i.e., cognitive control) and emotional development (i.e., emotion regulation) in the first years of life. The construct of temperament was used to unify cognition and emotion because of its focus on attentional and regulatory behaviors. Children were seen at 8 months and 4 1/2-years of…

Defining Transcriptional Regulatory Mechanisms for Primary let-7 miRNAs

PubMed Central

Gaeta, Xavier; Le, Luat; Lin, Ying; Xie, Yuan; Lowry, William E.

2017-01-01

The let-7 family of miRNAs have been shown to control developmental timing in organisms from C. elegans to humans; their function in several essential cell processes throughout development is also well conserved. Numerous studies have defined several steps of post-transcriptional regulation of let-7 production; from pri-miRNA through pre-miRNA, to the mature miRNA that targets endogenous mRNAs for degradation or translational inhibition. Less-well defined are modes of transcriptional regulation of the pri-miRNAs for let-7. let-7 pri-miRNAs are expressed in polycistronic fashion, in long transcripts newly annotated based on chromatin-associated RNA-sequencing. Upon differentiation, we found that some let-7 pri-miRNAs are regulated at the transcriptional level, while others appear to be constitutively transcribed. Using the Epigenetic Roadmap database, we further annotated regulatory elements of each polycistron identified putative promoters and enhancers. Probing these regulatory elements for transcription factor binding sites identified factors that regulate transcription of let-7 in both promoter and enhancer regions, and identified novel regulatory mechanisms for this important class of miRNAs. PMID:28052101

Live Imaging-Based Model Selection Reveals Periodic Regulation of the Stochastic G1/S Phase Transition in Vertebrate Axial Development

PubMed Central

Kurokawa, Hiroshi; Sakaue-Sawano, Asako; Imamura, Takeshi; Miyawaki, Atsushi; Iimura, Tadahiro

2014-01-01

In multicellular organism development, a stochastic cellular response is observed, even when a population of cells is exposed to the same environmental conditions. Retrieving the spatiotemporal regulatory mode hidden in the heterogeneous cellular behavior is a challenging task. The G1/S transition observed in cell cycle progression is a highly stochastic process. By taking advantage of a fluorescence cell cycle indicator, Fucci technology, we aimed to unveil a hidden regulatory mode of cell cycle progression in developing zebrafish. Fluorescence live imaging of Cecyil, a zebrafish line genetically expressing Fucci, demonstrated that newly formed notochordal cells from the posterior tip of the embryonic mesoderm exhibited the red (G1) fluorescence signal in the developing notochord. Prior to their initial vacuolation, these cells showed a fluorescence color switch from red to green, indicating G1/S transitions. This G1/S transition did not occur in a synchronous manner, but rather exhibited a stochastic process, since a mixed population of red and green cells was always inserted between newly formed red (G1) notochordal cells and vacuolating green cells. We termed this mixed population of notochordal cells, the G1/S transition window. We first performed quantitative analyses of live imaging data and a numerical estimation of the probability of the G1/S transition, which demonstrated the existence of a posteriorly traveling regulatory wave of the G1/S transition window. To obtain a better understanding of this regulatory mode, we constructed a mathematical model and performed a model selection by comparing the results obtained from the models with those from the experimental data. Our analyses demonstrated that the stochastic G1/S transition window in the notochord travels posteriorly in a periodic fashion, with doubled the periodicity of the neighboring paraxial mesoderm segmentation. This approach may have implications for the characterization of the pathophysiological tissue growth mode. PMID:25474567

The impact of transposable elements on mammalian development.

PubMed

Garcia-Perez, Jose L; Widmann, Thomas J; Adams, Ian R

2016-11-15

Despite often being classified as selfish or junk DNA, transposable elements (TEs) are a group of abundant genetic sequences that have a significant impact on mammalian development and genome regulation. In recent years, our understanding of how pre-existing TEs affect genome architecture, gene regulatory networks and protein function during mammalian embryogenesis has dramatically expanded. In addition, the mobilization of active TEs in selected cell types has been shown to generate genetic variation during development and in fully differentiated tissues. Importantly, the ongoing domestication and evolution of TEs appears to provide a rich source of regulatory elements, functional modules and genetic variation that fuels the evolution of mammalian developmental processes. Here, we review the functional impact that TEs exert on mammalian developmental processes and discuss how the somatic activity of TEs can influence gene regulatory networks. © 2016. Published by The Company of Biologists Ltd.

Knowledge enabled plan of care and documentation prototype.

PubMed

DaDamio, Rebecca; Gugerty, Brian; Kennedy, Rosemary

2006-01-01

There exist significant challenges in integrating the plan of care into documentation and point of care operational processes. A plan of care is often a static artifact that meets regulatory standards with limited influence on supporting goal-directed care delivery processes. Although this prototype is applicable to many clinical disciplines, we will highlight nursing processes in demonstrating a knowledge-driven computerized solution that fully integrates the plan of care within documentation. The knowledge-driven solution reflects evidenced-based practice; is an effective tool for managing problems, orders/interventions, and the patient's progress towards expected outcomes; meets regulatory standards; and drives quality and process improvement. The knowledge infrastructure consists of fully represented terminology, structured clinical expressions utilizing the controlled terminology and clinical knowledge representing evidence-based practice.

Regulative recovery in the sea urchin embryo and the stabilizing role of fail-safe gene network wiring

PubMed Central

Smith, Joel; Davidson, Eric H.

2009-01-01

Design features that ensure reproducible and invariant embryonic processes are major characteristics of current gene regulatory network models. New cis-regulatory studies on a gene regulatory network subcircuit activated early in the development of the sea urchin embryo reveal a sequence of encoded “fail-safe” regulatory devices. These ensure the maintenance of fate separation between skeletogenic and nonskeletogenic mesoderm lineages. An unexpected consequence of the network design revealed in the course of these experiments is that it enables the embryo to “recover” from regulatory interference that has catastrophic effects if this feature is disarmed. A reengineered regulatory system inserted into the embryo was used to prove how this system operates in vivo. Genomically encoded backup control circuitry thus provides the mechanism underlying a specific example of the regulative development for which the sea urchin embryo has long been famous. PMID:19822764

Transforming nanomedicine manufacturing toward Quality by Design and microfluidics.

PubMed

Colombo, Stefano; Beck-Broichsitter, Moritz; Bøtker, Johan Peter; Malmsten, Martin; Rantanen, Jukka; Bohr, Adam

2018-04-05

Nanopharmaceuticals aim at translating the unique features of nano-scale materials into therapeutic products and consequently their development relies critically on the progression in manufacturing technology to allow scalable processes complying with process economy and quality assurance. The relatively high failure rate in translational nanopharmaceutical research and development, with respect to new products on the market, is at least partly due to immature bottom-up manufacturing development and resulting sub-optimal control of quality attributes in nanopharmaceuticals. Recently, quality-oriented manufacturing of pharmaceuticals has undergone an unprecedented change toward process and product development interaction. In this context, Quality by Design (QbD) aims to integrate product and process development resulting in an increased number of product applications to regulatory agencies and stronger proprietary defense strategies of process-based products. Although QbD can be applied to essentially any production approach, microfluidic production offers particular opportunities for QbD-based manufacturing of nanopharmaceuticals. Microfluidics provides unique design flexibility, process control and parameter predictability, and also offers ample opportunities for modular production setups, allowing process feedback for continuously operating production and process control. The present review aims at outlining emerging opportunities in the synergistic implementation of QbD strategies and microfluidic production in contemporary development and manufacturing of nanopharmaceuticals. In doing so, aspects of design and development, but also technology management, are reviewed, as is the strategic role of these tools for aligning nanopharmaceutical innovation, development, and advanced industrialization in the broader pharmaceutical field. Copyright © 2018 Elsevier B.V. All rights reserved.

Unlocking Potentials of Microwaves for Food Safety and Quality

PubMed Central

Tang, Juming

2015-01-01

Microwave is an effective means to deliver energy to food through polymeric package materials, offering potential for developing short-time in-package sterilization and pasteurization processes. The complex physics related to microwave propagation and microwave heating require special attention to the design of process systems and development of thermal processes in compliance with regulatory requirements for food safety. This article describes the basic microwave properties relevant to heating uniformity and system design, and provides a historical overview on the development of microwave-assisted thermal sterilization (MATS) and pasteurization systems in research laboratories and used in food plants. It presents recent activities on the development of 915 MHz single-mode MATS technology, the procedures leading to regulatory acceptance, and sensory results of the processed products. The article discusses needs for further efforts to bridge remaining knowledge gaps and facilitate transfer of academic research to industrial implementation. PMID:26242920

Unlocking Potentials of Microwaves for Food Safety and Quality.

PubMed

Tang, Juming

2015-08-01

Microwave is an effective means to deliver energy to food through polymeric package materials, offering potential for developing short-time in-package sterilization and pasteurization processes. The complex physics related to microwave propagation and microwave heating require special attention to the design of process systems and development of thermal processes in compliance with regulatory requirements for food safety. This article describes the basic microwave properties relevant to heating uniformity and system design, and provides a historical overview on the development of microwave-assisted thermal sterilization (MATS) and pasteurization systems in research laboratories and used in food plants. It presents recent activities on the development of 915 MHz single-mode MATS technology, the procedures leading to regulatory acceptance, and sensory results of the processed products. The article discusses needs for further efforts to bridge remaining knowledge gaps and facilitate transfer of academic research to industrial implementation. © 2015 Institute of Food Technologists®

Evolutionary Insights into RNA trans-Splicing in Vertebrates

PubMed Central

Lei, Quan; Li, Cong; Zuo, Zhixiang; Huang, Chunhua; Cheng, Hanhua; Zhou, Rongjia

2016-01-01

Pre-RNA splicing is an essential step in generating mature mRNA. RNA trans-splicing combines two separate pre-mRNA molecules to form a chimeric non-co-linear RNA, which may exert a function distinct from its original molecules. Trans-spliced RNAs may encode novel proteins or serve as noncoding or regulatory RNAs. These novel RNAs not only increase the complexity of the proteome but also provide new regulatory mechanisms for gene expression. An increasing amount of evidence indicates that trans-splicing occurs frequently in both physiological and pathological processes. In addition, mRNA reprogramming based on trans-splicing has been successfully applied in RNA-based therapies for human genetic diseases. Nevertheless, clarifying the extent and evolution of trans-splicing in vertebrates and developing detection methods for trans-splicing remain challenging. In this review, we summarize previous research, highlight recent advances in trans-splicing, and discuss possible splicing mechanisms and functions from an evolutionary viewpoint. PMID:26966239

Advancing regulatory science to bring novel medical devices for use in emergency care to market: the role of the Food and Drug Administration.

PubMed

Scully, Christopher G; Forrest, Shawn; Galeotti, Loriano; Schwartz, Suzanne B; Strauss, David G

2015-04-01

The Food and Drug Administration (FDA) performs regulatory science to provide science-based medical product regulatory decisions. This article describes the types of scientific research the FDA's Center for Devices and Radiological Health performs and highlights specific projects related to medical devices for emergency medicine. In addition, this article discusses how results from regulatory science are used by the FDA to support the regulatory process as well as how the results are communicated to the public. Regulatory science supports the FDA's mission to assure safe, effective, and high-quality medical products are available to patients. Published by Elsevier Inc.

COMPUTER-AIDED DRUG DISCOVERY AND DEVELOPMENT (CADDD): in silico-chemico-biological approach

PubMed Central

Kapetanovic, I.M.

2008-01-01

It is generally recognized that drug discovery and development are very time and resources consuming processes. There is an ever growing effort to apply computational power to the combined chemical and biological space in order to streamline drug discovery, design, development and optimization. In biomedical arena, computer-aided or in silico design is being utilized to expedite and facilitate hit identification, hit-to-lead selection, optimize the absorption, distribution, metabolism, excretion and toxicity profile and avoid safety issues. Commonly used computational approaches include ligand-based drug design (pharmacophore, a 3-D spatial arrangement of chemical features essential for biological activity), structure-based drug design (drug-target docking), and quantitative structure-activity and quantitative structure-property relationships. Regulatory agencies as well as pharmaceutical industry are actively involved in development of computational tools that will improve effectiveness and efficiency of drug discovery and development process, decrease use of animals, and increase predictability. It is expected that the power of CADDD will grow as the technology continues to evolve. PMID:17229415

The development of regulatory expectations for computer-based safety systems for the UK nuclear programme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hughes, P. J.; Westwood, R.N; Mark, R. T.

2006-07-01

The Nuclear Installations Inspectorate (NII) of the UK's Health and Safety Executive (HSE) has completed a review of their Safety Assessment Principles (SAPs) for Nuclear Installations recently. During the period of the SAPs review in 2004-2005 the designers of future UK naval reactor plant were optioneering the control and protection systems that might be implemented. Because there was insufficient regulatory guidance available in the naval sector to support this activity the Defence Nuclear Safety Regulator (DNSR) invited the NII to collaborate with the production of a guidance document that provides clarity of regulatory expectations for the production of safety casesmore » for computer based safety systems. A key part of producing regulatory expectations was identifying the relevant extant standards and sector guidance that reflect good practice. The three principal sources of such good practice were: IAEA Safety Guide NS-G-1.1 (Software for Computer Based Systems Important to Safety in Nuclear Power Plants), European Commission consensus document (Common Position of European Nuclear Regulators for the Licensing of Safety Critical Software for Nuclear Reactors) and IEC nuclear sector standards such as IEC60880. A common understanding has been achieved between the NII and DNSR and regulatory guidance developed which will be used by both NII and DNSR in the assessment of computer-based safety systems and in the further development of more detailed joint technical assessment guidance for both regulatory organisations. (authors)« less

A Legislative Reform for the Food Safety System of China: A Regulatory Paradigm Shift and Collaborative Governance.

PubMed

Han, Yonghong

2015-01-01

After describing the historical development of China's food safety system from the perspectives of legislation and administration, this article discusses progress in its food law (The Draft Amendments to Food Safety Law). As a further legislative reform for China's food safety system, the Draft Amendments to the Food Safety Law contain innovative institutional designs and manifest a regulatory paradigm shift from government-centered governance to collaborative governance. However, the Draft Amendments face challenges in their implementation. This article argues that developing collaborative governance for food safety in China can be a solution to these challenges. Based on theoretical and empirical studies of collaborative governance, this article proposes that the institutional design of collaborative governance should focus on providing obligations for administrative agencies in the process of food safety rule-making and standard-setting, increasing the independence of nongovernmental organizations, and building two-way electronic platforms for public participation.

Continuous Manufacturing in Pharmaceutical Process Development and Manufacturing.

PubMed

Burcham, Christopher L; Florence, Alastair J; Johnson, Martin D

2018-06-07

The pharmaceutical industry has found new applications for the use of continuous processing for the manufacture of new therapies currently in development. The transformation has been encouraged by regulatory bodies as well as driven by cost reduction, decreased development cycles, access to new chemistries not practical in batch, improved safety, flexible manufacturing platforms, and improved product quality assurance. The transformation from batch to continuous manufacturing processing is the focus of this review. The review is limited to small, chemically synthesized organic molecules and encompasses the manufacture of both active pharmaceutical ingredients (APIs) and the subsequent drug product. Continuous drug product is currently used in approved processes. A few examples of production of APIs under current good manufacturing practice conditions using continuous processing steps have been published in the past five years, but they are lagging behind continuous drug product with respect to regulatory filings.

Genetically engineered crops for biofuel production: regulatory perspectives.

PubMed

Lee, David; Chen, Alice; Nair, Ramesh

2008-01-01

There are numerous challenges in realizing the potential of biofuels that many policy makers have envisioned. The technical challenges in making the production of biofuels economical and on a scale to replace a significant fraction of transportation fuel have been well described, along with the potential environmental concerns. The use of biotechnology can potentially address many of these technical challenges and environmental concerns, but brings significant regulatory hurdles that have not been discussed extensively in the scientific community. This review will give an overview of the approaches being developed to produce transgenic biofuel feedstocks, particularly cellulosic ethanol, and the regulatory process in the United States that oversees the development and commercialization of new transgenic plants. We hope to illustrate that the level of regulation for transgenic organisms is not proportional to their potential risk to human health or the environment, and that revisions to the regulatory system in the U.S. currently under consideration are necessary to streamline the process.

Applying Evolutionary Prototyping In Developing LMIS: A Spatial Web-Based System For Land Management

NASA Astrophysics Data System (ADS)

Agustiono, W.

2018-01-01

Software development project is a difficult task. Especially for software designed to comply with regulations that are constantly being introduced or changed, it is almost impossible to make just one change during the development process. Even if it is possible, nonetheless, the developers may take bulk of works to fix the design to meet specified needs. This iterative work also means that it takes additional time and potentially leads to failing to meet the original schedule and budget. In such inevitable changes, it is essential for developers to carefully consider and use an appropriate method which will help them carry out software project development. This research aims to examine the implementation of a software development method called evolutionary prototyping for developing software for complying regulation. It investigates the development of Land Management Information System (pseudonym), initiated by the Australian government, for use by farmers to meet regulatory demand requested by Soil and Land Conservation Act. By doing so, it sought to provide understanding the efficacy of evolutionary prototyping in helping developers address frequent changing requirements and iterative works but still within schedule. The findings also offer useful practical insights for other developers who seek to build similar regulatory compliance software.

Implantation of an ergonomics administration system in a company: report of an occupational therapist specialist in ergonomics.

PubMed

Moraes, Berla; Andrade, Valéria Sousa

2012-01-01

This article aims to describe step-by-step the implementation of an ergonomics administration system in a company from March 2009 till March 2011 by an occupational therapist specialist in ergonomics based on the OSHAS 18001 guidelines and the Regulatory Norms 17 manual. The process began with the definition of five requisites with bases on the manual of application of the Regulatory Norms 17: survey; materials individual transportation and discharge; workplace furniture; workplace equipments; work environment and organization of the work to be managed with bases on the OSHAS 18001 guidelines. The following steps were established: sensitization of the company high administration, elaboration and institution of an ergonomics politics, development of ergonomics committees, ergonomics analysis of the work with recommendation of ergonomic improvements, implantation of improvements and evaluation or the results. This research experiment suggests the importance not only of a guiding axle but also of a professional qualification and participation of the company on the implementation of an ergonomics management system.

Identifying significant genetic regulatory networks in the prostate cancer from microarray data based on transcription factor analysis and conditional independency.

PubMed

Yeh, Hsiang-Yuan; Cheng, Shih-Wu; Lin, Yu-Chun; Yeh, Cheng-Yu; Lin, Shih-Fang; Soo, Von-Wun

2009-12-21

Prostate cancer is a world wide leading cancer and it is characterized by its aggressive metastasis. According to the clinical heterogeneity, prostate cancer displays different stages and grades related to the aggressive metastasis disease. Although numerous studies used microarray analysis and traditional clustering method to identify the individual genes during the disease processes, the important gene regulations remain unclear. We present a computational method for inferring genetic regulatory networks from micorarray data automatically with transcription factor analysis and conditional independence testing to explore the potential significant gene regulatory networks that are correlated with cancer, tumor grade and stage in the prostate cancer. To deal with missing values in microarray data, we used a K-nearest-neighbors (KNN) algorithm to determine the precise expression values. We applied web services technology to wrap the bioinformatics toolkits and databases to automatically extract the promoter regions of DNA sequences and predicted the transcription factors that regulate the gene expressions. We adopt the microarray datasets consists of 62 primary tumors, 41 normal prostate tissues from Stanford Microarray Database (SMD) as a target dataset to evaluate our method. The predicted results showed that the possible biomarker genes related to cancer and denoted the androgen functions and processes may be in the development of the prostate cancer and promote the cell death in cell cycle. Our predicted results showed that sub-networks of genes SREBF1, STAT6 and PBX1 are strongly related to a high extent while ETS transcription factors ELK1, JUN and EGR2 are related to a low extent. Gene SLC22A3 may explain clinically the differentiation associated with the high grade cancer compared with low grade cancer. Enhancer of Zeste Homolg 2 (EZH2) regulated by RUNX1 and STAT3 is correlated to the pathological stage. We provide a computational framework to reconstruct the genetic regulatory network from the microarray data using biological knowledge and constraint-based inferences. Our method is helpful in verifying possible interaction relations in gene regulatory networks and filtering out incorrect relations inferred by imperfect methods. We predicted not only individual gene related to cancer but also discovered significant gene regulation networks. Our method is also validated in several enriched published papers and databases and the significant gene regulatory networks perform critical biological functions and processes including cell adhesion molecules, androgen and estrogen metabolism, smooth muscle contraction, and GO-annotated processes. Those significant gene regulations and the critical concept of tumor progression are useful to understand cancer biology and disease treatment.

Science-based regulatory and policy considerations in nutrition.

PubMed

Schneeman, Barbara

2015-05-01

Scientific evidence is necessary for the development of effective and enforceable regulations and government policy. To use scientific information appropriately, a systematic approach is needed for review and evaluation of the evidence. Federal agencies in the United States have developed useful approaches for such a review and evaluation to develop nutrition labeling, including health claims, and for updating of the Dietary Guidelines for Americans. The WHO is using a systematic evaluation process to update its recommendations on diet and health. The results of such reviews also highlight research needs to address relevant gaps in our knowledge. © 2015 American Society for Nutrition.

Beginning to manage drug discovery and development knowledge.

PubMed

Sumner-Smith, M

2001-05-01

Knowledge management approaches and technologies are beginning to be implemented by the pharmaceutical industry in support of new drug discovery and development processes aimed at greater efficiencies and effectiveness. This trend coincides with moves to reduce paper, coordinate larger teams with more diverse skills that are distributed around the globe, and to comply with regulatory requirements for electronic submissions and the associated maintenance of electronic records. Concurrently, the available technologies have implemented web-based architectures with a greater range of collaborative tools and personalization through portal approaches. However, successful application of knowledge management methods depends on effective cultural change management, as well as proper architectural design to match the organizational and work processes within a company.

Moving new vaccines for tuberculosis through the regulatory process.

PubMed

Brennan, M J

2000-06-01

The development of novel vaccines for the prevention of tuberculosis is an area of intense interest for scientific researchers, public health agencies, and pharmaceutical manufacturers. Development of effective new vaccines directed against tuberculosis for use in target populations will require close cooperation among several different international organizations, including regulatory agencies responsible for evaluating the safety and effectiveness of new biologics for human use.

USING CFD TO ANALYZE NUCLEAR SYSTEMS BEHAVIOR: DEFINING THE VALIDATION REQUIREMENTS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Richard Schultz

2012-09-01

A recommended protocol to formulate numeric tool specifications and validation needs in concert with practices accepted by regulatory agencies for advanced reactors is described. The protocol is based on the plant type and perceived transient and accident envelopes that translates to boundary conditions for a process that gives the: (a) key phenomena and figures-of-merit which must be analyzed to ensure that the advanced plant can be licensed, (b) specification of the numeric tool capabilities necessary to perform the required analyses—including bounding calculational uncertainties, and (c) specification of the validation matrices and experiments--including the desired validation data. The result of applyingmore » the process enables a complete program to be defined, including costs, for creating and benchmarking transient and accident analysis methods for advanced reactors. By following a process that is in concert with regulatory agency licensing requirements from the start to finish, based on historical acceptance of past licensing submittals, the methods derived and validated have a high probability of regulatory agency acceptance.« less

TranscriptomeBrowser 3.0: introducing a new compendium of molecular interactions and a new visualization tool for the study of gene regulatory networks.

PubMed

Lepoivre, Cyrille; Bergon, Aurélie; Lopez, Fabrice; Perumal, Narayanan B; Nguyen, Catherine; Imbert, Jean; Puthier, Denis

2012-01-31

Deciphering gene regulatory networks by in silico approaches is a crucial step in the study of the molecular perturbations that occur in diseases. The development of regulatory maps is a tedious process requiring the comprehensive integration of various evidences scattered over biological databases. Thus, the research community would greatly benefit from having a unified database storing known and predicted molecular interactions. Furthermore, given the intrinsic complexity of the data, the development of new tools offering integrated and meaningful visualizations of molecular interactions is necessary to help users drawing new hypotheses without being overwhelmed by the density of the subsequent graph. We extend the previously developed TranscriptomeBrowser database with a set of tables containing 1,594,978 human and mouse molecular interactions. The database includes: (i) predicted regulatory interactions (computed by scanning vertebrate alignments with a set of 1,213 position weight matrices), (ii) potential regulatory interactions inferred from systematic analysis of ChIP-seq experiments, (iii) regulatory interactions curated from the literature, (iv) predicted post-transcriptional regulation by micro-RNA, (v) protein kinase-substrate interactions and (vi) physical protein-protein interactions. In order to easily retrieve and efficiently analyze these interactions, we developed In-teractomeBrowser, a graph-based knowledge browser that comes as a plug-in for Transcriptome-Browser. The first objective of InteractomeBrowser is to provide a user-friendly tool to get new insight into any gene list by providing a context-specific display of putative regulatory and physical interactions. To achieve this, InteractomeBrowser relies on a "cell compartments-based layout" that makes use of a subset of the Gene Ontology to map gene products onto relevant cell compartments. This layout is particularly powerful for visual integration of heterogeneous biological information and is a productive avenue in generating new hypotheses. The second objective of InteractomeBrowser is to fill the gap between interaction databases and dynamic modeling. It is thus compatible with the network analysis software Cytoscape and with the Gene Interaction Network simulation software (GINsim). We provide examples underlying the benefits of this visualization tool for large gene set analysis related to thymocyte differentiation. The InteractomeBrowser plugin is a powerful tool to get quick access to a knowledge database that includes both predicted and validated molecular interactions. InteractomeBrowser is available through the TranscriptomeBrowser framework and can be found at: http://tagc.univ-mrs.fr/tbrowser/. Our database is updated on a regular basis.

Integrating Data Clustering and Visualization for the Analysis of 3D Gene Expression Data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Data Analysis and Visualization; nternational Research Training Group ``Visualization of Large and Unstructured Data Sets,'' University of Kaiserslautern, Germany; Computational Research Division, Lawrence Berkeley National Laboratory, One Cyclotron Road, Berkeley, CA 94720, USA

2008-05-12

The recent development of methods for extracting precise measurements of spatial gene expression patterns from three-dimensional (3D) image data opens the way for new analyses of the complex gene regulatory networks controlling animal development. We present an integrated visualization and analysis framework that supports user-guided data clustering to aid exploration of these new complex datasets. The interplay of data visualization and clustering-based data classification leads to improved visualization and enables a more detailed analysis than previously possible. We discuss (i) integration of data clustering and visualization into one framework; (ii) application of data clustering to 3D gene expression data; (iii)more » evaluation of the number of clusters k in the context of 3D gene expression clustering; and (iv) improvement of overall analysis quality via dedicated post-processing of clustering results based on visualization. We discuss the use of this framework to objectively define spatial pattern boundaries and temporal profiles of genes and to analyze how mRNA patterns are controlled by their regulatory transcription factors.« less

A perspective on the benefit-risk assessment for new and emerging pharmaceuticals in Japan.

PubMed

Tanimoto, Tetsuya

2015-01-01

The universal health care system in Japan is facing a historical turning point as a result of the increasing fiscal burden, rapidly aging society, and a decreasing population. To understand the challenges and opportunities in the Japanese pharmaceutical market, which occupies one tenth of the global share, this review highlights several issues related to the benefit-risk assessment that is unique to the modern Japanese society: 1) regulatory system for new drug development; 2) health hazards related to pharmaceuticals ("Yakugai" in Japanese); 3) drug lag; 4) problems and controversies in the vaccination policy; and 5) clinical study misconduct. The regulatory process places a significant importance on Japanese data collection regardless of data accumulation from other countries. Because Yakugai has repeatedly caused tragedies and social disputes historically, the regulatory judgments generally tend to be more prudential when safety concerns are raised for new and emerging pharmaceuticals. Such a regulatory system has caused more than several years of approval delays compared to delays in other countries. The problem of drug lag still lingers on despite several regulatory system revisions, while the solution is incompatible with the elimination of Yakugai because the lag potentially reduces the risk of unpredictable adverse events. The Japanese vaccination policy has also received a lot of criticism, and needs improvements so that the decision-making process can be more transparent and scientifically based. Additionally, repeated clinical study misconduct damaged the reputation of Japanese clinical studies with unnecessary defrayment in health insurance; therefore, the medical community must change its inappropriate relationship with the industry. The problems surrounding pharmaceuticals are related to centralized, strict drug pricing control under the universal health coverage. Although the current government attempts to facilitate innovative research and development of novel therapeutics in Japan, further reforms should be explored for patients who need new and emerging pharmaceuticals.

A perspective on the benefit-risk assessment for new and emerging pharmaceuticals in Japan

PubMed Central

Tanimoto, Tetsuya

2015-01-01

The universal health care system in Japan is facing a historical turning point as a result of the increasing fiscal burden, rapidly aging society, and a decreasing population. To understand the challenges and opportunities in the Japanese pharmaceutical market, which occupies one tenth of the global share, this review highlights several issues related to the benefit-risk assessment that is unique to the modern Japanese society: 1) regulatory system for new drug development; 2) health hazards related to pharmaceuticals (“Yakugai” in Japanese); 3) drug lag; 4) problems and controversies in the vaccination policy; and 5) clinical study misconduct. The regulatory process places a significant importance on Japanese data collection regardless of data accumulation from other countries. Because Yakugai has repeatedly caused tragedies and social disputes historically, the regulatory judgments generally tend to be more prudential when safety concerns are raised for new and emerging pharmaceuticals. Such a regulatory system has caused more than several years of approval delays compared to delays in other countries. The problem of drug lag still lingers on despite several regulatory system revisions, while the solution is incompatible with the elimination of Yakugai because the lag potentially reduces the risk of unpredictable adverse events. The Japanese vaccination policy has also received a lot of criticism, and needs improvements so that the decision-making process can be more transparent and scientifically based. Additionally, repeated clinical study misconduct damaged the reputation of Japanese clinical studies with unnecessary defrayment in health insurance; therefore, the medical community must change its inappropriate relationship with the industry. The problems surrounding pharmaceuticals are related to centralized, strict drug pricing control under the universal health coverage. Although the current government attempts to facilitate innovative research and development of novel therapeutics in Japan, further reforms should be explored for patients who need new and emerging pharmaceuticals. PMID:25848223

Transcriptional regulatory proteins as biosensing tools.

PubMed

Turner, Kendrick; Joel, Smita; Feliciano, Jessika; Feltus, Agatha; Pasini, Patrizia; Wynn, Daniel; Dau, Peter; Dikici, Emre; Deo, Sapna K; Daunert, Sylvia

2017-06-22

We have developed sensing systems employing different classes of transcriptional regulatory proteins genetically and chemically modified to incorporate a fluorescent reporter molecule for detection of arsenic, hydroxylated polychlorinated biphenyls (OH-PCBs), and cyclic AMP (cAMP). These are the first examples of optical sensing systems based on transcriptional regulatory proteins.

Regulatory ozone modeling: status, directions, and research needs.

PubMed Central

Georgopoulos, P G

1995-01-01

The Clean Air Act Amendments (CAAA) of 1990 have established selected comprehensive, three-dimensional, Photochemical Air Quality Simulation Models (PAQSMs) as the required regulatory tools for analyzing the urban and regional problem of high ambient ozone levels across the United States. These models are currently applied to study and establish strategies for meeting the National Ambient Air Quality Standard (NAAQS) for ozone in nonattainment areas; State Implementation Plans (SIPs) resulting from these efforts must be submitted to the U.S. Environmental Protection Agency (U.S. EPA) in November 1994. The following presentation provides an overview and discussion of the regulatory ozone modeling process and its implications. First, the PAQSM-based ozone attainment demonstration process is summarized in the framework of the 1994 SIPs. Then, following a brief overview of the representation of physical and chemical processes in PAQSMs, the essential attributes of standard modeling systems currently in regulatory use are presented in a nonmathematical, self-contained format, intended to provide a basic understanding of both model capabilities and limitations. The types of air quality, emission, and meteorological data needed for applying and evaluating PAQSMs are discussed, as well as the sources, availability, and limitations of existing databases. The issue of evaluating a model's performance in order to accept it as a tool for policy making is discussed, and various methodologies for implementing this objective are summarized. Selected interim results from diagnostic analyses, which are performed as a component of the regulatory ozone modeling process for the Philadelphia-New Jersey region, are also presented to provide some specific examples related to the general issues discussed in this work. Finally, research needs related to a) the evaluation and refinement of regulatory ozone modeling, b) the characterization of uncertainty in photochemical modeling, and c) the improvement of the model-based ozone-attainment demonstration process are presented to identify future directions in this area. Images Figure 7. Figure 7. Figure 7. Figure 8. Figure 9. PMID:7614934

Sequence-based model of gap gene regulatory network.

PubMed

Kozlov, Konstantin; Gursky, Vitaly; Kulakovskiy, Ivan; Samsonova, Maria

2014-01-01

The detailed analysis of transcriptional regulation is crucially important for understanding biological processes. The gap gene network in Drosophila attracts large interest among researches studying mechanisms of transcriptional regulation. It implements the most upstream regulatory layer of the segmentation gene network. The knowledge of molecular mechanisms involved in gap gene regulation is far less complete than that of genetics of the system. Mathematical modeling goes beyond insights gained by genetics and molecular approaches. It allows us to reconstruct wild-type gene expression patterns in silico, infer underlying regulatory mechanism and prove its sufficiency. We developed a new model that provides a dynamical description of gap gene regulatory systems, using detailed DNA-based information, as well as spatial transcription factor concentration data at varying time points. We showed that this model correctly reproduces gap gene expression patterns in wild type embryos and is able to predict gap expression patterns in Kr mutants and four reporter constructs. We used four-fold cross validation test and fitting to random dataset to validate the model and proof its sufficiency in data description. The identifiability analysis showed that most model parameters are well identifiable. We reconstructed the gap gene network topology and studied the impact of individual transcription factor binding sites on the model output. We measured this impact by calculating the site regulatory weight as a normalized difference between the residual sum of squares error for the set of all annotated sites and for the set with the site of interest excluded. The reconstructed topology of the gap gene network is in agreement with previous modeling results and data from literature. We showed that 1) the regulatory weights of transcription factor binding sites show very weak correlation with their PWM score; 2) sites with low regulatory weight are important for the model output; 3) functional important sites are not exclusively located in cis-regulatory elements, but are rather dispersed through regulatory region. It is of importance that some of the sites with high functional impact in hb, Kr and kni regulatory regions coincide with strong sites annotated and verified in Dnase I footprint assays.

A Review of the Environmental Impacts for Marine and Hydrokinetic Projects to Inform Regulatory Permitting: Summary Findings from the 2015 Workshop on Marine and Hydrokinetic Technologies, Washington, D.C.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baring-Gould, E. Ian; Christol, Corrie; LiVecchi, Al

In 2014 and 2015, the U.S. Department of Energy initiated efforts to develop and implement technology- and application-focused marine and hydrokinetic (MHK) workshops to share the global experience and knowledge base on evolving MHK technologies, observed and not-observed impacts, monitoring and measurement methods, and regulatory needs. The resulting MHK Regulator Workshops engaged resource managers and other decision makers at key regulatory organizations, scientists, researchers, facilitators, and technical experts and provided an opportunity to examine the risks of single-device and small-scale deployments, explore what can be learned and observed from single devices and small-scale arrays, and consider requirements for projects atmore » varying scales of deployment. Experts and stakeholders identified key remaining information gaps. Initial discussions focused on differentiating between monitoring required for single or small-scale deployments and MHK impact research that, although important, goes beyond what is feasible or should be needed to meet specific project regulatory requirements but is appropriate for broader research and development. Four areas of identified potential environmental impacts provided the focus for the workshop: acoustic output impacts, electromagnetic field (EMF) emissions, physical interactions, and environmental effects of MHK energy development on the physical environment. Discussions also focused on the regulatory process and experience, adaptive management, industry drivers, and lessons that can be learned from the wind energy industry. The discussion was set in the context of the types of MHK technologies that are currently proposed or planned in the United States. All presentations and the following discussions are summarized in this document.« less

Emergent self-regulatory activity among young children during scientific inquiry: An analysis of six kindergarten children

NASA Astrophysics Data System (ADS)

Lomangino, Adrienne Gelpi

2000-10-01

This qualitative investigation extends the study of self-regulation to examine young children's developing self-regulated learning competencies. The framework for this research draws upon social cognitive, developmental, and sociocultural perspectives on self-regulation and research on children's scientific thinking. Taking a multiple case study approach, this study examines six kindergarten children's emerging self-regulatory competencies during inquiry-based science instruction. Data were collected during two inquiry-based science programs of study, one pertaining to light and shadow and a second pertaining to motion on inclined planes. Data sources included: videotaped records of the instruction, transcriptions of the videotapes, interviews with the children and teacher, student work, and field notes. Taking an inductive approach to analysis, patterns in the children's activity were identified through a recursive process of defining and refining categories that characterized the children's verbal and behavioral activity. Each case study examines a child's behavior within each phase of the inquiry for evidence of emerging self-regulatory competence. Analysis revealed nascent forms of goal-setting and planning, monitoring, resource management, seeking social assistance, and evaluating. Monitoring activity occurred more frequently than planning or evaluating. For several children, animating materials served to promote motivation. Children's efforts to support peers' activity and monitor the meaning of ongoing discourse contrast with common assumptions about children's attention to others' thinking. Variations in self-regulatory activity were found across phases of instruction. The children exhibited interpersonal self-regulatory efforts, in which monitoring and control of the self was entwined with the activity of others. Joint participation also played a critical role in supporting the metacognitive demands of self-regulation and prompting metacognitive awareness. However, planning and self-evaluation were constrained by the opportunities provided within the instruction for engaging in self-regulatory activity.

Sharing regulatory data as tools for strengthening health systems in the Region of the Americas.

PubMed

Sousa, Varley Dias; Ramalho, Pedro I; Silveira, Dâmaris

2016-05-01

Regulatory transparency is an imperative characteristic of a reliable National Regulatory Authority. In the region of the Americas, the process of building an open government is still fragile and fragmented across various Health Regulatory Agencies (HRAs) and Regional Reference Authorities (RRAs). This study assessed the transparency status of RRAs, focusing on various medicine life-cycle documents (the Medicine Dossier, Clinical Trial Report, and Inspection Report) as tools for strengthening health systems. Based on a narrative (nonsystematic) review of RRA regulatory transparency, transparency status was classified as one of two types: public disclosure of information (intra-agency data) and data- and work-sharing (inter-agency data). The risks/benefits of public disclosure of medicine-related information were assessed, taking into account 1) the involvement and roles of multiple stakeholders (health care professionals, regulators, industry, community, and academics) and 2) the protection of commercial and personal confidential data. Inter-agency data- and work-sharing was evaluated in the context of harmonization and cooperation projects that focus on regulatory convergence. Technical and practical steps for establishing an openness directive for the pharmaceutical regulatory environment are proposed to improve and strengthen health systems in the Americas. Addressing these challenges requires leadership from entities such as the Pan American Health Organization to steer and support collaborative regional alliances that advance the development and establishment of a trustworthy regulatory environment and a sustainable public health system in the Americas, using international successful initiatives as reference and taking into account the domestic characteristics and experiences of each individual country.

Approaches for Increasing Acceptance of Physiologically Based Pharmacokinetic Models in Public Health Risk Assessment

EPA Science Inventory

Physiologically based pharmacokinetic (PBPK) models have great potential for application in regulatory and non-regulatory public health risk assessment. The development and application of PBPK models in chemical toxicology has grown steadily since their emergence in the 1980s. Ho...

Scientific basis for risk analysis of food-related substances with particular reference to health effects on children.

PubMed

Hayashi, Yuzo

2009-01-01

Based on the advance of toxicology and related sciences, a regulatory regime for the safety of chemicals related to daily life has been rapidly established. Especially for the food-related substances, the process of risk analysis has facilitated the collaboration by all the players including consumers toward the security of their safety. On the other hand, except for pharmaceuticals, science-based decisions and governmental actions on safety issues have not always gained confidence of the public. One of the reasons was the inadequacy in the way of use of scientific knowledge, or in other words, inappropriateness of decision making by "the regulatory science". Regulatory science is a science to warrant the decision making processes for governmental acts (Mitsuru Uchiyama). In the case of chemical safety, it can be redefined as a theoretical concept to complements the uncertainty of scientific knowledge for the decision of governmental acts that is adequate in both scientific and social ways. Therefore, the regulatory science is an indispensable discipline to effectively apply risk analysis. Here, the significance of the regulatory science for the hazard assessment of the chemicals, especially for children is described. In the past, the hazard effects of chemicals have been assessed for adults. Recently, however, the importance of the assessment for children has gained international emphases. Not only for pharmaceuticals, but for food-related substances, the acceptable daily intake (ADI) and tolerable daily intake (TDI) are often set differently for adults and children. The child-specific responses against chemicals are related not only to the physiological factors such as body weight, basal metabolism, but also rapid growth of the body with developmental status of various organs. General knowledge on these issues will be discussed mainly referring the World Health Organization (WHO) documents. Although the cutting edge technology backs up the development of toxicology, it would appear that it is reaching a turning point from technology-centrism to look toward the direction for contribution to society from the stand point of regulatory science.

Biotechnology and the bioeconomy-Towards inclusive and sustainable industrial development.

PubMed

Lokko, Yvonne; Heijde, Marc; Schebesta, Karl; Scholtès, Philippe; Van Montagu, Marc; Giacca, Mauro

2018-01-25

To transform developing and least developing countries into industrialised ones, biotechnology could be deployed along the value chain, to provide support to the development of the bio-based industries in such a way to ensure sustainability of the sector and to reduce negative environmental impacts that might otherwise occur. In agribusiness development, for instance, interventions could start from inputs and agricultural mechanization, modern processing technologies, packaging of perishable products, the promotion of food safety in the processing and regulatory environment; and interventions to improve competitiveness and productivity. Worth over USD 300 billion in revenue, the role of the biotechnology goes beyond industrial growth, since it provides opportunities for progress towards many of the UN sustainable development goals (SDGs). This paper reviews the status of industrial biotechnology as it relates to inclusive and sustainable industrial development. Copyright © 2017 Elsevier B.V. All rights reserved.

Drug reformulations and repositioning in the pharmaceutical industry and their impact on market access: regulatory implications

PubMed Central

Murteira, Susana; Millier, Aurélie; Ghezaiel, Zied; Lamure, Michel

2014-01-01

Background Repurposing has become a mainstream strategy in drug development, but it faces multiple challenges, amongst them the increasing and ever changing regulatory framework. This is the second study of a series of three-part publication project with the ultimate goal of understanding the market access rationale and conditions attributed to drug repurposing in the United States and in Europe. The aim of the current study to evaluate the regulatory path associated with each type of repurposing strategy according to the previously proposed nomenclature in the first article of this series. Methods From the cases identified, a selection process retrieved a total of 141 case studies in all countries, harmonized for data availability and common approval in the United States and in Europe. Regulatory information for each original and repurposed drug product was extracted, and several related regulatory attributes were also extracted such as, designation change and filing before or after patent expiry, among others. Descriptive analyses were conducted to determine trends and to investigate potential associations between the different regulatory paths and attributes of interest, for reformulation and repositioning cases separately. Results Within the studied European countries, most of the applications for reformulated products were filed through national applications. In contrast, for repositioned products, the centralized procedure was the most frequent regulatory pathway. Most of the repurposing cases were approved before patent expiry, and those cases have followed more complex regulatory pathways in the United States and in Europe. For new molecular entities filed in the United States, a similar number of cases were developed by serendipity and by a hypothesis-driven approach. However, for the new indication's regulatory pathway in the United States, most of the cases were developed through a hypothesis-driven approach. Conclusion The regulations in the United States and in Europe for drug repositionings and reformulations allowed confirming that repositioning strategies were usually filed under a more complex regulatory process than reformulations. Also, it seems that parameters such as patent expiry and type of repositioning approach or reformulation affect the regulatory pathways chosen for each case. PMID:27226839

76 FR 78706 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving a...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-19

... incorporated NYSE Rule 2A (Jurisdiction) as part of the process of developing a consolidated rulebook..., among other things, rulemaking, examinations, disciplinary actions, and listing applications. NYSE Rule... executives, employees and approved persons in connection with their conduct of the business of member...

30 CFR 939.764 - Process for designating areas unsuitable for surface coal mining operations.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Mining Operations, pertaining to petitioning, initial processing, hearing requirements, decisions, data base and inventory systems, public information, and regulatory responsibilities shall become applicable...

30 CFR 903.764 - Process for designating areas unsuitable for surface coal mining operations.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Mining Operations, pertaining to petitions, initial processing, hearing requirements, decisions, data base and inventory systems, public information, and regulatory responsibilities, applies to surface...

30 CFR 939.764 - Process for designating areas unsuitable for surface coal mining operations.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Mining Operations, pertaining to petitioning, initial processing, hearing requirements, decisions, data base and inventory systems, public information, and regulatory responsibilities shall become applicable...

30 CFR 903.764 - Process for designating areas unsuitable for surface coal mining operations.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Mining Operations, pertaining to petitions, initial processing, hearing requirements, decisions, data base and inventory systems, public information, and regulatory responsibilities, applies to surface...

30 CFR 903.764 - Process for designating areas unsuitable for surface coal mining operations.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Mining Operations, pertaining to petitions, initial processing, hearing requirements, decisions, data base and inventory systems, public information, and regulatory responsibilities, applies to surface...

30 CFR 939.764 - Process for designating areas unsuitable for surface coal mining operations.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Mining Operations, pertaining to petitioning, initial processing, hearing requirements, decisions, data base and inventory systems, public information, and regulatory responsibilities shall become applicable...

30 CFR 939.764 - Process for designating areas unsuitable for surface coal mining operations.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Mining Operations, pertaining to petitioning, initial processing, hearing requirements, decisions, data base and inventory systems, public information, and regulatory responsibilities shall become applicable...

30 CFR 939.764 - Process for designating areas unsuitable for surface coal mining operations.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Mining Operations, pertaining to petitioning, initial processing, hearing requirements, decisions, data base and inventory systems, public information, and regulatory responsibilities shall become applicable...

30 CFR 903.764 - Process for designating areas unsuitable for surface coal mining operations.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Mining Operations, pertaining to petitions, initial processing, hearing requirements, decisions, data base and inventory systems, public information, and regulatory responsibilities, applies to surface...

Building quality into medical product software design.

PubMed

Mallory, S R

1993-01-01

The software engineering and quality assurance disciplines are a requisite to the design of safe and effective software-based medical devices. It is in the areas of software methodology and process that the most beneficial application of these disciplines to software development can be made. Software is a product of complex operations and methodologies and is not amenable to the traditional electromechanical quality assurance processes. Software quality must be built in by the developers, with the software verification and validation engineers acting as the independent instruments for ensuring compliance with performance objectives and with development and maintenance standards. The implementation of a software quality assurance program is a complex process involving management support, organizational changes, and new skill sets, but the benefits are profound. Its rewards provide safe, reliable, cost-effective, maintainable, and manageable software, which may significantly speed the regulatory review process and therefore potentially shorten the overall time to market. The use of a trial project can greatly facilitate the learning process associated with the first-time application of a software quality assurance program.

Development and testing of the VITAMIN-B7/BUGLE-B7 coupled neutron-gamma multigroup cross-section libraries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Risner, J.M.; Wiarda, D.; Miller, T.M.

2011-07-01

The U.S. Nuclear Regulatory Commission's Regulatory Guide 1.190 states that calculational methods used to estimate reactor pressure vessel (RPV) fluence should use the latest version of the evaluated nuclear data file (ENDF). The VITAMIN-B6 fine-group library and BUGLE-96 broad-group library, which are widely used for RPV fluence calculations, were generated using ENDF/B-VI.3 data, which was the most current data when Regulatory Guide 1.190 was issued. We have developed new fine-group (VITAMIN-B7) and broad-group (BUGLE-B7) libraries based on ENDF/B-VII.0. These new libraries, which were processed using the AMPX code system, maintain the same group structures as the VITAMIN-B6 and BUGLE-96 libraries.more » Verification and validation of the new libraries were accomplished using diagnostic checks in AMPX, 'unit tests' for each element in VITAMIN-B7, and a diverse set of benchmark experiments including critical evaluations for fast and thermal systems, a set of experimental benchmarks that are used for SCALE regression tests, and three RPV fluence benchmarks. The benchmark evaluation results demonstrate that VITAMIN-B7 and BUGLE-B7 are appropriate for use in RPV fluence calculations and meet the calculational uncertainty criterion in Regulatory Guide 1.190. (authors)« less

Development and Testing of the VITAMIN-B7/BUGLE-B7 Coupled Neutron-Gamma Multigroup Cross-Section Libraries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Risner, Joel M; Wiarda, Dorothea; Miller, Thomas Martin

2011-01-01

The U.S. Nuclear Regulatory Commission s Regulatory Guide 1.190 states that calculational methods used to estimate reactor pressure vessel (RPV) fluence should use the latest version of the Evaluated Nuclear Data File (ENDF). The VITAMIN-B6 fine-group library and BUGLE-96 broad-group library, which are widely used for RPV fluence calculations, were generated using ENDF/B-VI data, which was the most current data when Regulatory Guide 1.190 was issued. We have developed new fine-group (VITAMIN-B7) and broad-group (BUGLE-B7) libraries based on ENDF/B-VII. These new libraries, which were processed using the AMPX code system, maintain the same group structures as the VITAMIN-B6 and BUGLE-96more » libraries. Verification and validation of the new libraries was accomplished using diagnostic checks in AMPX, unit tests for each element in VITAMIN-B7, and a diverse set of benchmark experiments including critical evaluations for fast and thermal systems, a set of experimental benchmarks that are used for SCALE regression tests, and three RPV fluence benchmarks. The benchmark evaluation results demonstrate that VITAMIN-B7 and BUGLE-B7 are appropriate for use in LWR shielding applications, and meet the calculational uncertainty criterion in Regulatory Guide 1.190.« less

Integrating Transcriptomic and Proteomic Data Using Predictive Regulatory Network Models of Host Response to Pathogens

PubMed Central

Chasman, Deborah; Walters, Kevin B.; Lopes, Tiago J. S.; Eisfeld, Amie J.; Kawaoka, Yoshihiro; Roy, Sushmita

2016-01-01

Mammalian host response to pathogenic infections is controlled by a complex regulatory network connecting regulatory proteins such as transcription factors and signaling proteins to target genes. An important challenge in infectious disease research is to understand molecular similarities and differences in mammalian host response to diverse sets of pathogens. Recently, systems biology studies have produced rich collections of omic profiles measuring host response to infectious agents such as influenza viruses at multiple levels. To gain a comprehensive understanding of the regulatory network driving host response to multiple infectious agents, we integrated host transcriptomes and proteomes using a network-based approach. Our approach combines expression-based regulatory network inference, structured-sparsity based regression, and network information flow to infer putative physical regulatory programs for expression modules. We applied our approach to identify regulatory networks, modules and subnetworks that drive host response to multiple influenza infections. The inferred regulatory network and modules are significantly enriched for known pathways of immune response and implicate apoptosis, splicing, and interferon signaling processes in the differential response of viral infections of different pathogenicities. We used the learned network to prioritize regulators and study virus and time-point specific networks. RNAi-based knockdown of predicted regulators had significant impact on viral replication and include several previously unknown regulators. Taken together, our integrated analysis identified novel module level patterns that capture strain and pathogenicity-specific patterns of expression and helped identify important regulators of host response to influenza infection. PMID:27403523

Delayed access to treatments for rare diseases: who's to blame?

PubMed

Feltmate, Karen; Janiszewski, Peter M; Gingerich, Sheena; Cloutier, Michael

2015-04-01

The development and commercialization of drugs for rare diseases, termed 'orphan drugs', has historically been economically unattractive. However, because of the introduction of legislation that provides financial and regulatory incentives for the development of orphan drugs, new developments are making their way through the regulatory approval processes. Unfortunately, delays in availability of new drugs for treating rare disease continue to persist. This paper reviews the approach of several regulatory jurisdictions to orphan drugs in an effort to determine their relative effectiveness in providing patient access. Generally speaking, regulatory authorities across jurisdictions have recognized the need to enhance timely access to safe, effective treatment for patients with rare diseases and have been able to shift the approval timelines for access to new care. The greater impediment to orphan drug access appears to be funding, particularly in publicly sponsored health-care systems. Redundancies in federal and provincial reviews of orphan drugs can result in significant delays in access to new drugs. Clearly, more must be done to accelerate access to the treatments so desperately needed by patients. Public payers must be held accountable for their process and decisions--especially for rare disease therapies. © 2015 Asian Pacific Society of Respirology.

Sensitivity, child regulatory processes, and naturally occurring declines in antisocial behavior across childhood.

PubMed

Buck, Katharine Ann

2014-12-01

Despite considerable research on why antisocial behavior develops and interventions that reduce it, aspects of everyday family processes that may promote naturally occurring declines in antisocial behavior or that may result from such declines in most children without intervention are poorly understood. The current study explored family processes that may enable children to replace antisocial tendencies and the effects that declines in antisocial behavior may have on parenting and child regulatory processes. Longitudinal data from 1,022 children (54 months-6th grade) from the NICHD Study of Early Child Care and Youth Development were examined. Findings demonstrated that naturally occurring declines in antisocial behavior both predicted and were predicted by maternal sensitivity, emotion regulation, and social skills. These declines predicted but were not predicted by declines in hostile attributions. The data revealed multiple indirect paths, which highlight the complex nature of these variables across development.

Dynamic Maternal Gradients Control Timing and Shift-Rates for Drosophila Gap Gene Expression

PubMed Central

Verd, Berta; Crombach, Anton

2017-01-01

Pattern formation during development is a highly dynamic process. In spite of this, few experimental and modelling approaches take into account the explicit time-dependence of the rules governing regulatory systems. We address this problem by studying dynamic morphogen interpretation by the gap gene network in Drosophila melanogaster. Gap genes are involved in segment determination during early embryogenesis. They are activated by maternal morphogen gradients encoded by bicoid (bcd) and caudal (cad). These gradients decay at the same time-scale as the establishment of the antero-posterior gap gene pattern. We use a reverse-engineering approach, based on data-driven regulatory models called gene circuits, to isolate and characterise the explicitly time-dependent effects of changing morphogen concentrations on gap gene regulation. To achieve this, we simulate the system in the presence and absence of dynamic gradient decay. Comparison between these simulations reveals that maternal morphogen decay controls the timing and limits the rate of gap gene expression. In the anterior of the embyro, it affects peak expression and leads to the establishment of smooth spatial boundaries between gap domains. In the posterior of the embryo, it causes a progressive slow-down in the rate of gap domain shifts, which is necessary to correctly position domain boundaries and to stabilise the spatial gap gene expression pattern. We use a newly developed method for the analysis of transient dynamics in non-autonomous (time-variable) systems to understand the regulatory causes of these effects. By providing a rigorous mechanistic explanation for the role of maternal gradient decay in gap gene regulation, our study demonstrates that such analyses are feasible and reveal important aspects of dynamic gene regulation which would have been missed by a traditional steady-state approach. More generally, it highlights the importance of transient dynamics for understanding complex regulatory processes in development. PMID:28158178

Dynamic Maternal Gradients Control Timing and Shift-Rates for Drosophila Gap Gene Expression.

PubMed

Verd, Berta; Crombach, Anton; Jaeger, Johannes

2017-02-01

Pattern formation during development is a highly dynamic process. In spite of this, few experimental and modelling approaches take into account the explicit time-dependence of the rules governing regulatory systems. We address this problem by studying dynamic morphogen interpretation by the gap gene network in Drosophila melanogaster. Gap genes are involved in segment determination during early embryogenesis. They are activated by maternal morphogen gradients encoded by bicoid (bcd) and caudal (cad). These gradients decay at the same time-scale as the establishment of the antero-posterior gap gene pattern. We use a reverse-engineering approach, based on data-driven regulatory models called gene circuits, to isolate and characterise the explicitly time-dependent effects of changing morphogen concentrations on gap gene regulation. To achieve this, we simulate the system in the presence and absence of dynamic gradient decay. Comparison between these simulations reveals that maternal morphogen decay controls the timing and limits the rate of gap gene expression. In the anterior of the embyro, it affects peak expression and leads to the establishment of smooth spatial boundaries between gap domains. In the posterior of the embryo, it causes a progressive slow-down in the rate of gap domain shifts, which is necessary to correctly position domain boundaries and to stabilise the spatial gap gene expression pattern. We use a newly developed method for the analysis of transient dynamics in non-autonomous (time-variable) systems to understand the regulatory causes of these effects. By providing a rigorous mechanistic explanation for the role of maternal gradient decay in gap gene regulation, our study demonstrates that such analyses are feasible and reveal important aspects of dynamic gene regulation which would have been missed by a traditional steady-state approach. More generally, it highlights the importance of transient dynamics for understanding complex regulatory processes in development.

Multi-Hazard Advanced Seismic Probabilistic Risk Assessment Tools and Applications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coleman, Justin L.; Bolisetti, Chandu; Veeraraghavan, Swetha

Design of nuclear power plant (NPP) facilities to resist natural hazards has been a part of the regulatory process from the beginning of the NPP industry in the United States (US), but has evolved substantially over time. The original set of approaches and methods was entirely deterministic in nature and focused on a traditional engineering margins-based approach. However, over time probabilistic and risk-informed approaches were also developed and implemented in US Nuclear Regulatory Commission (NRC) guidance and regulation. A defense-in-depth framework has also been incorporated into US regulatory guidance over time. As a result, today, the US regulatory framework incorporatesmore » deterministic and probabilistic approaches for a range of different applications and for a range of natural hazard considerations. This framework will continue to evolve as a result of improved knowledge and newly identified regulatory needs and objectives, most notably in response to the NRC activities developed in response to the 2011 Fukushima accident in Japan. Although the US regulatory framework has continued to evolve over time, the tools, methods and data available to the US nuclear industry to meet the changing requirements have not kept pace. Notably, there is significant room for improvement in the tools and methods available for external event probabilistic risk assessment (PRA), which is the principal assessment approach used in risk-informed regulations and risk-informed decision-making applied to natural hazard assessment and design. This is particularly true if PRA is applied to natural hazards other than seismic loading. Development of a new set of tools and methods that incorporate current knowledge, modern best practice, and state-of-the-art computational resources would lead to more reliable assessment of facility risk and risk insights (e.g., the SSCs and accident sequences that are most risk-significant), with less uncertainty and reduced conservatisms.« less

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2013-07-01

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30 CFR 922.764 - Process for designating areas unsuitable for surface coal mining operations.

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2014-07-01

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30 CFR 912.764 - Process for designating areas unsuitable for surface coal mining operations.

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Guidelines for performing systematic reviews in the development of toxicity factors.

PubMed

Schaefer, Heather R; Myers, Jessica L

2017-12-01

The Texas Commission on Environmental Quality (TCEQ) developed guidance on conducting systematic reviews during the development of chemical-specific toxicity factors. Using elements from publicly available frameworks, the TCEQ systematic review process was developed in order to supplement the existing TCEQ Guidelines for developing toxicity factors (TCEQ Regulatory Guidance 442). The TCEQ systematic review process includes six steps: 1) Problem Formulation; 2) Systematic Literature Review and Study Selection; 3) Data Extraction; 4) Study Quality and Risk of Bias Assessment; 5) Evidence Integration and Endpoint Determination; and 6) Confidence Rating. This document provides guidance on conducting a systematic literature review and integrating evidence from different data streams when developing chemical-specific reference values (ReVs) and unit risk factors (URFs). However, this process can also be modified or expanded to address other questions that would benefit from systematic review practices. The systematic review and evidence integration framework can improve regulatory decision-making processes, increase transparency, minimize bias, improve consistency between different risk assessments, and further improve confidence in toxicity factor development. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

The Long and Winding Road to Innovation.

PubMed

Beyar, Rafael

2015-07-30

Medicine is developing through biomedical technology and innovations. The goal of any innovation in medicine is to improve patient care. Exponential growth in technology has led to the unprecedented growth of medical technology over the last 50 years. Clinician-scientists need to understand the complexity of the innovation process, from concept to product release, when working to bring new clinical solutions to the bedside. Hence, an overview of the innovation process is provided herein. The process involves an invention designed to solve an unmet need, followed by prototype design and optimization, animal studies, pilot and pivotal studies, and regulatory approval. The post-marketing strategy relative to funding, along with analysis of cost benefit, is a critical component for the adoption of new technologies. Examples of the road to innovation are provided, based on the experience with development of the transcatheter aortic valve. Finally, ideas are presented to contribute to the further development of this worldwide trend in innovation.

The Long and Winding Road to Innovation

PubMed Central

Beyar, Rafael

2015-01-01

Medicine is developing through biomedical technology and innovations. The goal of any innovation in medicine is to improve patient care. Exponential growth in technology has led to the unprecedented growth of medical technology over the last 50 years. Clinician-scientists need to understand the complexity of the innovation process, from concept to product release, when working to bring new clinical solutions to the bedside. Hence, an overview of the innovation process is provided herein. The process involves an invention designed to solve an unmet need, followed by prototype design and optimization, animal studies, pilot and pivotal studies, and regulatory approval. The post-marketing strategy relative to funding, along with analysis of cost benefit, is a critical component for the adoption of new technologies. Examples of the road to innovation are provided, based on the experience with development of the transcatheter aortic valve. Finally, ideas are presented to contribute to the further development of this worldwide trend in innovation. PMID:26241234

The role of stakeholders in developing an international regulatory framework for carbon capture and storage

NASA Astrophysics Data System (ADS)

Augustin, C. M.; Broad, K.; Swart, P. K.

2011-12-01

It is estimated that carbon capture and storage (CCS) could be used to achieve between 15% and 55% of the carbon emission reductions necessary to avoid dangerous levels of climate change. It is also believed that achieving emission reduction goals will be less costly with CCS than without it. The expansion of active CCS sites over the past decade, from three to 53 demonstrates the value that industry sees in CCS as a transition technology for governments seeking to reduce their CO2 emissions. However, to continue developing CCS for industry scale implementation, it is essential to provide the regulatory certainty needed to foster energy industry wide adoption of CCS. Existing CCS regulatory regimes are inadequate, fragmented and contradictory. There is a need for comprehensive, unifying regulations for CCS that are flexible enough to adapt as the technology develops. Governments are limited by the fact that carbon capture and storage is a multidisciplinary issue that touches on the fields of oil drilling, groundwater quality, greenhouse gas management, air quality, and risk management. Though it is in part a technological, environmental and management issue there is also a complex political element to tackling the CCS problem. Due to its cross-cutting nature, CCS regulations should be based off the best practices and standards developed by industry stakeholders. Industry standards are stakeholder developed and consensus based, created through a democratic and collaborative process by bodies such as the International Standards Organization, the National Institutes of Standards and Testing (USA), ASTM International, and the Canadian Standards Organization. Standards can typically be broken down into six general categories: test methods, specifications, classifications, practices, guides, and terminology. These standards are created by stakeholders across the industry and across geographic boundaries to create an trade-wide, rather than nationwide, consensus and ensuring that the standards are international in scope. This paper examines regulatory issues post-capture, particularly the transport and geological storage of carbon dioxide and seeks to identify areas where relevant stakeholders should collaborate to develop a comprehensive list of industry standards and provides several case study examples.

The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension.

PubMed

Lennernäs, Hans; Abrahamsson, Bertil

2005-03-01

Bioavailability (BA) and bioequivalence (BE) play a central role in pharmaceutical product development and BE studies are presently being conducted for New Drug Applications (NDAs) of new compounds, in supplementary NDAs for new medical indications and product line extensions, in Abbreviated New Drug Applications (ANDAs) of generic products and in applications for scale-up and post-approval changes. The Biopharmaceutics Classification System (BCS) has been developed to provide a scientific approach for classifying drug compounds based on solubility as related to dose and intestinal permeability in combination with the dissolution properties of the oral immediaterelease (IR) dosage form. The aim of the BCS is to provide a regulatory tool for replacing certain BE studies by accurate in-vitro dissolution tests. The aim of this review is to present the status of the BCS and discuss its future application in pharmaceutical product development. The future application of the BCS is most likely increasingly important when the present framework gains increased recognition, which will probably be the case if the BCS borders for certain class II and III drugs are extended. The future revision of the BCS guidelines by the regulatory agencies in communication with academic and industrial scientists is exciting and will hopefully result in an increased applicability in drug development. Finally, we emphasize the great use of the BCS as a simple tool in early drug development to determine the rate-limiting step in the oral absorption process, which has facilitated the information between different experts involved in the overall drug development process. This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in drug molecules with a sufficiently high permeability, solubility and dissolution rate, and that will automatically increase the importance of the BCS as a regulatory tool over time.

Analytical quality by design: a tool for regulatory flexibility and robust analytics.

PubMed

Peraman, Ramalingam; Bhadraya, Kalva; Padmanabha Reddy, Yiragamreddy

2015-01-01

Very recently, Food and Drug Administration (FDA) has approved a few new drug applications (NDA) with regulatory flexibility for quality by design (QbD) based analytical approach. The concept of QbD applied to analytical method development is known now as AQbD (analytical quality by design). It allows the analytical method for movement within method operable design region (MODR). Unlike current methods, analytical method developed using analytical quality by design (AQbD) approach reduces the number of out-of-trend (OOT) results and out-of-specification (OOS) results due to the robustness of the method within the region. It is a current trend among pharmaceutical industry to implement analytical quality by design (AQbD) in method development process as a part of risk management, pharmaceutical development, and pharmaceutical quality system (ICH Q10). Owing to the lack explanatory reviews, this paper has been communicated to discuss different views of analytical scientists about implementation of AQbD in pharmaceutical quality system and also to correlate with product quality by design and pharmaceutical analytical technology (PAT).

Analytical Quality by Design: A Tool for Regulatory Flexibility and Robust Analytics

PubMed Central

Bhadraya, Kalva; Padmanabha Reddy, Yiragamreddy

2015-01-01

Very recently, Food and Drug Administration (FDA) has approved a few new drug applications (NDA) with regulatory flexibility for quality by design (QbD) based analytical approach. The concept of QbD applied to analytical method development is known now as AQbD (analytical quality by design). It allows the analytical method for movement within method operable design region (MODR). Unlike current methods, analytical method developed using analytical quality by design (AQbD) approach reduces the number of out-of-trend (OOT) results and out-of-specification (OOS) results due to the robustness of the method within the region. It is a current trend among pharmaceutical industry to implement analytical quality by design (AQbD) in method development process as a part of risk management, pharmaceutical development, and pharmaceutical quality system (ICH Q10). Owing to the lack explanatory reviews, this paper has been communicated to discuss different views of analytical scientists about implementation of AQbD in pharmaceutical quality system and also to correlate with product quality by design and pharmaceutical analytical technology (PAT). PMID:25722723

Data Quality Objectives for Regulatory Requirements for Dangerous Waste Sampling and Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

MULKEY, C.H.

1999-07-02

This document describes sampling and analytical requirements needed to meet state and federal regulations for dangerous waste (DW). The River Protection Project (RPP) is assigned to the task of storage and interim treatment of hazardous waste. Any final treatment or disposal operations, as well as requirements under the land disposal restrictions (LDRs), fall in the jurisdiction of another Hanford organization and are not part of this scope. The requirements for this Data Quality Objective (DQO) Process were developed using the RPP Data Quality Objective Procedure (Banning 1996), which is based on the U.S. Environmental Protection Agency's (EPA) Guidance for themore » Data Quality Objectives Process (EPA 1994). Hereafter, this document is referred to as the DW DQO. Federal and state laws and regulations pertaining to waste contain requirements that are dependent upon the composition of the waste stream. These regulatory drivers require that pertinent information be obtained. For many requirements, documented process knowledge of a waste composition can be used instead of analytical data to characterize or designate a waste. When process knowledge alone is used to characterize a waste, it is a best management practice to validate the information with analytical measurements.« less

An Initial Evaluation of Siting Considerations on Current and Future Wind Deployment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tegen, Suzanne; Lantz, Eric; Mai, Trieu

This report provides a deeper understanding of the wind project development process, from desktop studies to a successful project in the ground. It examines three siting consideration categories that wind project sponsors must include in the development process: wildlife (species that live in, near, or migrate through the area where wind development is possible), radar (wind turbines can cause interference with radar signals), and public engagement (representing communities and stakeholders who live near wind power projects). The research shows that although this country's abundant wind resource provides numerous options for addressing siting considerations, actually siting individual projects is becoming moremore » difficult because of regulatory and other uncertainties. Model results are based on the premise that developers will be able to site, permit, and build successful projects, which is not always the case in reality.« less

Genomic control of patterning

PubMed Central

Peter, Isabelle S.; Davidson, Eric H.

2014-01-01

The development of multicellular organisms involves the partitioning of the organism into territories of cells of specific structure and function. The information for spatial patterning processes is directly encoded in the genome. The genome determines its own usage depending on stage and position, by means of interactions that constitute gene regulatory networks (GRNs). The GRN driving endomesoderm development in sea urchin embryos illustrates different regulatory strategies by which developmental programs are initiated, orchestrated, stabilized or excluded to define the pattern of specified territories in the developing embryo. PMID:19378258

A cis-regulatory logic simulator.

PubMed

Zeigler, Robert D; Gertz, Jason; Cohen, Barak A

2007-07-27

A major goal of computational studies of gene regulation is to accurately predict the expression of genes based on the cis-regulatory content of their promoters. The development of computational methods to decode the interactions among cis-regulatory elements has been slow, in part, because it is difficult to know, without extensive experimental validation, whether a particular method identifies the correct cis-regulatory interactions that underlie a given set of expression data. There is an urgent need for test expression data in which the interactions among cis-regulatory sites that produce the data are known. The ability to rapidly generate such data sets would facilitate the development and comparison of computational methods that predict gene expression patterns from promoter sequence. We developed a gene expression simulator which generates expression data using user-defined interactions between cis-regulatory sites. The simulator can incorporate additive, cooperative, competitive, and synergistic interactions between regulatory elements. Constraints on the spacing, distance, and orientation of regulatory elements and their interactions may also be defined and Gaussian noise can be added to the expression values. The simulator allows for a data transformation that simulates the sigmoid shape of expression levels from real promoters. We found good agreement between sets of simulated promoters and predicted regulatory modules from real expression data. We present several data sets that may be useful for testing new methodologies for predicting gene expression from promoter sequence. We developed a flexible gene expression simulator that rapidly generates large numbers of simulated promoters and their corresponding transcriptional output based on specified interactions between cis-regulatory sites. When appropriate rule sets are used, the data generated by our simulator faithfully reproduces experimentally derived data sets. We anticipate that using simulated gene expression data sets will facilitate the direct comparison of computational strategies to predict gene expression from promoter sequence. The source code is available online and as additional material. The test sets are available as additional material.

Development of World Health Organization (WHO) recommendations for appropriate clinical trial endpoints for next-generation Human Papillomavirus (HPV) vaccines.

PubMed

Prabhu, Malavika; Eckert, Linda O

2016-12-01

The World Health Organization (WHO) serves as a key organization to bring together experts along the continuum of vaccine development and regulatory approval, among its other functions. Using the revision of WHO's guidelines on prophylactic human papillomavirus (HPV) vaccine as an example, we describe the process by which (1) a need to revise the guidelines was identified; (2) a group of stakeholders with complementary expertise and key questions were identified; (3) a scientific review was conducted; (4) consensus on revisions was achieved; (5) guidelines were updated, reviewed widely, and approved. This multi-year process resulted in the consensus that regulatory agencies could consider additional endpoints, such as persistent HPV infection or immune equivalence, depending on the design of the HPV vaccine trials. Updating the guidelines will now accelerate vaccine development, reduce costs of clinical trials, and lead to faster regulatory approval. Copyright © 2016. Published by Elsevier B.V.

MESSI: metabolic engineering target selection and best strain identification tool.

PubMed

Kang, Kang; Li, Jun; Lim, Boon Leong; Panagiotou, Gianni

2015-01-01

Metabolic engineering and synthetic biology are synergistically related fields for manipulating target pathways and designing microorganisms that can act as chemical factories. Saccharomyces cerevisiae's ideal bioprocessing traits make yeast a very attractive chemical factory for production of fuels, pharmaceuticals, nutraceuticals as well as a wide range of chemicals. However, future attempts of engineering S. cerevisiae's metabolism using synthetic biology need to move towards more integrative models that incorporate the high connectivity of metabolic pathways and regulatory processes and the interactions in genetic elements across those pathways and processes. To contribute in this direction, we have developed Metabolic Engineering target Selection and best Strain Identification tool (MESSI), a web server for predicting efficient chassis and regulatory components for yeast bio-based production. The server provides an integrative platform for users to analyse ready-to-use public high-throughput metabolomic data, which are transformed to metabolic pathway activities for identifying the most efficient S. cerevisiae strain for the production of a compound of interest. As input MESSI accepts metabolite KEGG IDs or pathway names. MESSI outputs a ranked list of S. cerevisiae strains based on aggregation algorithms. Furthermore, through a genome-wide association study of the metabolic pathway activities with the strains' natural variation, MESSI prioritizes genes and small variants as potential regulatory points and promising metabolic engineering targets. Users can choose various parameters in the whole process such as (i) weight and expectation of each metabolic pathway activity in the final ranking of the strains, (ii) Weighted AddScore Fuse or Weighted Borda Fuse aggregation algorithm, (iii) type of variants to be included, (iv) variant sets in different biological levels.Database URL: http://sbb.hku.hk/MESSI/. © The Author(s) 2015. Published by Oxford University Press.

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

The role of the Radiation Safety Officer at a medical facility can be complicated. The complexity of the position is based on the breadth of services provided at the institution and the nature of the radioactive materials license. Medical practices are constantly changing and the use of ionizing radiation continues to rise in this area. Some of the newer medical applications involving radiation have unique regulatory and safety issues that must be addressed. Oversight of the uses of radiation start at the local level (radiation safety officer, radiation safety committee) and are heavily impacted by outside agencies (i.e. Nuclear Regulatorymore » Commission, State Radiologic Health, The Joint Commission (TJC), etc). This session will provide both an overview of regulatory oversight and essential compliance practices as well as practical ways to assess and introduce some of the new applications utilizing radioactive materials into your medical facility. Learning Objectives: Regulatory Compliance and Safety with New Radiotherapies: Spheres and Ra-223 (Lance Phillips) Understand the radioactive materials license amendment process to add new radiotherapies (i.e., SIR-Spheres, Therasphere, Xofigo). Understand the AU approval process for microspheres and Xofigo. Examine the training and handling requirements for new procedures. Understand the process involved with protocol development, SOP in order to define roles and responsibilities. The RSO and The RSC: Challenges and Opportunities (Colin Dimock) Understand how to form an effective Committee. Examine what the Committee does for the Program and the RSO. Understand the importance of Committee engagement. Discuss the balance of the complimentary roles of the RSO and the Committee. The Alphabet Soup of Regulatory Compliance: Being Prepared for Inspections (Linda Kroger) Recognize the various regulatory bodies and organizations with oversight or impact in Nuclear Medicine, Radiology and Radiation Oncology. Examine 10CFR35 requirements as they relate to the everyday practice of Nuclear Medicine and Radiation Oncology. Understand the nature of available guidance documents (e.g., NUREG 1556). Examine the commonalities between TJC and CMS preparedness.« less

MO-AB-201-02: The RSO and The RSC: Challenges and Opportunities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dimock, C.

2015-06-15

The role of the Radiation Safety Officer at a medical facility can be complicated. The complexity of the position is based on the breadth of services provided at the institution and the nature of the radioactive materials license. Medical practices are constantly changing and the use of ionizing radiation continues to rise in this area. Some of the newer medical applications involving radiation have unique regulatory and safety issues that must be addressed. Oversight of the uses of radiation start at the local level (radiation safety officer, radiation safety committee) and are heavily impacted by outside agencies (i.e. Nuclear Regulatorymore » Commission, State Radiologic Health, The Joint Commission (TJC), etc). This session will provide both an overview of regulatory oversight and essential compliance practices as well as practical ways to assess and introduce some of the new applications utilizing radioactive materials into your medical facility. Learning Objectives: Regulatory Compliance and Safety with New Radiotherapies: Spheres and Ra-223 (Lance Phillips) Understand the radioactive materials license amendment process to add new radiotherapies (i.e., SIR-Spheres, Therasphere, Xofigo). Understand the AU approval process for microspheres and Xofigo. Examine the training and handling requirements for new procedures. Understand the process involved with protocol development, SOP in order to define roles and responsibilities. The RSO and The RSC: Challenges and Opportunities (Colin Dimock) Understand how to form an effective Committee. Examine what the Committee does for the Program and the RSO. Understand the importance of Committee engagement. Discuss the balance of the complimentary roles of the RSO and the Committee. The Alphabet Soup of Regulatory Compliance: Being Prepared for Inspections (Linda Kroger) Recognize the various regulatory bodies and organizations with oversight or impact in Nuclear Medicine, Radiology and Radiation Oncology. Examine 10CFR35 requirements as they relate to the everyday practice of Nuclear Medicine and Radiation Oncology. Understand the nature of available guidance documents (e.g., NUREG 1556). Examine the commonalities between TJC and CMS preparedness.« less

Inferring causal genomic alterations in breast cancer using gene expression data

PubMed Central

2011-01-01

Background One of the primary objectives in cancer research is to identify causal genomic alterations, such as somatic copy number variation (CNV) and somatic mutations, during tumor development. Many valuable studies lack genomic data to detect CNV; therefore, methods that are able to infer CNVs from gene expression data would help maximize the value of these studies. Results We developed a framework for identifying recurrent regions of CNV and distinguishing the cancer driver genes from the passenger genes in the regions. By inferring CNV regions across many datasets we were able to identify 109 recurrent amplified/deleted CNV regions. Many of these regions are enriched for genes involved in many important processes associated with tumorigenesis and cancer progression. Genes in these recurrent CNV regions were then examined in the context of gene regulatory networks to prioritize putative cancer driver genes. The cancer driver genes uncovered by the framework include not only well-known oncogenes but also a number of novel cancer susceptibility genes validated via siRNA experiments. Conclusions To our knowledge, this is the first effort to systematically identify and validate drivers for expression based CNV regions in breast cancer. The framework where the wavelet analysis of copy number alteration based on expression coupled with the gene regulatory network analysis, provides a blueprint for leveraging genomic data to identify key regulatory components and gene targets. This integrative approach can be applied to many other large-scale gene expression studies and other novel types of cancer data such as next-generation sequencing based expression (RNA-Seq) as well as CNV data. PMID:21806811

A prior-based integrative framework for functional transcriptional regulatory network inference

PubMed Central

Siahpirani, Alireza F.

2017-01-01

Abstract Transcriptional regulatory networks specify regulatory proteins controlling the context-specific expression levels of genes. Inference of genome-wide regulatory networks is central to understanding gene regulation, but remains an open challenge. Expression-based network inference is among the most popular methods to infer regulatory networks, however, networks inferred from such methods have low overlap with experimentally derived (e.g. ChIP-chip and transcription factor (TF) knockouts) networks. Currently we have a limited understanding of this discrepancy. To address this gap, we first develop a regulatory network inference algorithm, based on probabilistic graphical models, to integrate expression with auxiliary datasets supporting a regulatory edge. Second, we comprehensively analyze our and other state-of-the-art methods on different expression perturbation datasets. Networks inferred by integrating sequence-specific motifs with expression have substantially greater agreement with experimentally derived networks, while remaining more predictive of expression than motif-based networks. Our analysis suggests natural genetic variation as the most informative perturbation for network inference, and, identifies core TFs whose targets are predictable from expression. Multiple reasons make the identification of targets of other TFs difficult, including network architecture and insufficient variation of TF mRNA level. Finally, we demonstrate the utility of our inference algorithm to infer stress-specific regulatory networks and for regulator prioritization. PMID:27794550

Intertemporal Regulatory Tasks and Responsibilities for Greenhouse Gas Reductions

ERIC Educational Resources Information Center

Deason, Jeffrey A.; Friedman, Lee S.

2010-01-01

Jurisdictions are in the process of establishing regulatory systems to control greenhouse gas emissions. Short-term and sometimes long-term emissions reduction goals are established, as California does for 2020 and 2050, but little attention has yet been focused on annual emissions targets for the intervening years. We develop recommendations for…

RCRA, superfund and EPCRA hotline training module. Introduction to: RCRA corrective action updated July 1996

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1996-07-01

The module discusses the regulatory and statutory requirements and authorities governing the Resource Conservation and Recovery Act (RCRA) corrective action process. There are minimal regulatory requirements at present, but the Agency has issued a proposed rule (55 FR 30798; July 27, 1990) that would establish a comprehensive regulatory framework for implementing the corrective action program. This proposed rule and other guidance developed pursuant to statutory authorities are used to structure corrective action requirements in facility permits and orders. This module describes the current statutory and regulatory structure and discusses the future of the proposed rule.

Process and product development in the manufacturing of molecular therapeutics.

PubMed

Atkinson, E M; Christensen, J R

1999-08-01

In the development of molecular therapies, a great deal of attention has focused on tissue targets, gene delivery vectors, and expression cassettes. In order to become an approved therapy, however, a molecular therapeutic has to pass down the same product registration pathway as any other biological product. Moving from research into industrial production requires careful attention to regulatory, manufacturing and quality concerns. Early work on developing and characterizing robust and scaleable manufacturing processes will ultimately be rewarded by ease of implementation as the product is successful in clinical trials. Regulatory agencies require solid process and product characterization studies to demonstrate control and understanding of the molecular therapeutic. As the gene therapy industry matures, standards will continue to rise, creating an industry that is capable of producing safe, high-quality and effective therapies for many of the world's most difficult disease targets.

Dynamics of the job search process: developing and testing a mediated moderation model.

PubMed

Sun, Shuhua; Song, Zhaoli; Lim, Vivien K G

2013-09-01

Taking a self-regulatory perspective, we develop a mediated moderation model explaining how within-person changes in job search efficacy and chronic regulatory focus interactively affect the number of job interview offers and whether job search effort mediates the cross-level interactive effects. A sample of 184 graduating college students provided monthly reports of their job search activities over a period of 8 months. Findings supported the hypothesized relationships. Specifically, at the within-person level, job search efficacy was positively related with the number of interview offers for job seekers with strong prevention focus and negatively related with the number of interview offers for job seekers with strong promotion focus. Results show that job search effort mediated the moderated relationships. Findings enhance understandings of the complex self-regulatory processes underlying job search. PsycINFO Database Record (c) 2013 APA, all rights reserved

A Bayesian Approach to Determination of F, D, and Z Values Used in Steam Sterilization Validation.

PubMed

Faya, Paul; Stamey, James D; Seaman, John W

2017-01-01

For manufacturers of sterile drug products, steam sterilization is a common method used to provide assurance of the sterility of manufacturing equipment and products. The validation of sterilization processes is a regulatory requirement and relies upon the estimation of key resistance parameters of microorganisms. Traditional methods have relied upon point estimates for the resistance parameters. In this paper, we propose a Bayesian method for estimation of the well-known D T , z , and F o values that are used in the development and validation of sterilization processes. A Bayesian approach allows the uncertainty about these values to be modeled using probability distributions, thereby providing a fully risk-based approach to measures of sterility assurance. An example is given using the survivor curve and fraction negative methods for estimation of resistance parameters, and we present a means by which a probabilistic conclusion can be made regarding the ability of a process to achieve a specified sterility criterion. LAY ABSTRACT: For manufacturers of sterile drug products, steam sterilization is a common method used to provide assurance of the sterility of manufacturing equipment and products. The validation of sterilization processes is a regulatory requirement and relies upon the estimation of key resistance parameters of microorganisms. Traditional methods have relied upon point estimates for the resistance parameters. In this paper, we propose a Bayesian method for estimation of the critical process parameters that are evaluated in the development and validation of sterilization processes. A Bayesian approach allows the uncertainty about these parameters to be modeled using probability distributions, thereby providing a fully risk-based approach to measures of sterility assurance. An example is given using the survivor curve and fraction negative methods for estimation of resistance parameters, and we present a means by which a probabilistic conclusion can be made regarding the ability of a process to achieve a specified sterility criterion. © PDA, Inc. 2017.

Drug interactions evaluation: An integrated part of risk assessment of therapeutics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Lei; Reynolds, Kellie S.; Zhao, Ping

2010-03-01

Pharmacokinetic drug interactions can lead to serious adverse events or decreased drug efficacy. The evaluation of a new molecular entity's (NME's) drug-drug interaction potential is an integral part of risk assessment during drug development and regulatory review. Alteration of activities of enzymes or transporters involved in the absorption, distribution, metabolism, or excretion of a new molecular entity by concomitant drugs may alter drug exposure, which can impact response (safety or efficacy). The recent Food and Drug Administration (FDA) draft drug interaction guidance ( (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf)) highlights the methodologies and criteria that may be used to guide drug interaction evaluation by industrymore » and regulatory agencies and to construct informative labeling for health practitioner and patients. In addition, the Food and Drug Administration established a 'Drug Development and Drug Interactions' website to provide up-to-date information regarding evaluation of drug interactions ( (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm)). This review summarizes key elements in the FDA drug interaction guidance and new scientific developments that can guide the evaluation of drug-drug interactions during the drug development process.« less

Long Noncoding RNAs: a New Regulatory Code in Metabolic Control

PubMed Central

Zhao, Xu-Yun; Lin, Jiandie D.

2015-01-01

Long noncoding RNAs (lncRNAs) are emerging as an integral part of the regulatory information encoded in the genome. LncRNAs possess the unique capability to interact with nucleic acids and proteins and exert discrete effects on numerous biological processes. Recent studies have delineated multiple lncRNA pathways that control metabolic tissue development and function. The expansion of the regulatory code that links nutrient and hormonal signals to tissue metabolism gives new insights into the genetic and pathogenic mechanisms underlying metabolic disease. This review discusses lncRNA biology with a focus on its role in the development, signaling, and function of key metabolic tissues. PMID:26410599

Efficient Reverse-Engineering of a Developmental Gene Regulatory Network

PubMed Central

Cicin-Sain, Damjan; Ashyraliyev, Maksat; Jaeger, Johannes

2012-01-01

Understanding the complex regulatory networks underlying development and evolution of multi-cellular organisms is a major problem in biology. Computational models can be used as tools to extract the regulatory structure and dynamics of such networks from gene expression data. This approach is called reverse engineering. It has been successfully applied to many gene networks in various biological systems. However, to reconstitute the structure and non-linear dynamics of a developmental gene network in its spatial context remains a considerable challenge. Here, we address this challenge using a case study: the gap gene network involved in segment determination during early development of Drosophila melanogaster. A major problem for reverse-engineering pattern-forming networks is the significant amount of time and effort required to acquire and quantify spatial gene expression data. We have developed a simplified data processing pipeline that considerably increases the throughput of the method, but results in data of reduced accuracy compared to those previously used for gap gene network inference. We demonstrate that we can infer the correct network structure using our reduced data set, and investigate minimal data requirements for successful reverse engineering. Our results show that timing and position of expression domain boundaries are the crucial features for determining regulatory network structure from data, while it is less important to precisely measure expression levels. Based on this, we define minimal data requirements for gap gene network inference. Our results demonstrate the feasibility of reverse-engineering with much reduced experimental effort. This enables more widespread use of the method in different developmental contexts and organisms. Such systematic application of data-driven models to real-world networks has enormous potential. Only the quantitative investigation of a large number of developmental gene regulatory networks will allow us to discover whether there are rules or regularities governing development and evolution of complex multi-cellular organisms. PMID:22807664

NICE technology appraisals: working with multiple levels of uncertainty and the potential for bias.

PubMed

Brown, Patrick; Calnan, Michael

2013-05-01

One of the key roles of the English National Institute for Health and Clinical Excellence (NICE) is technology appraisal. This essentially involves evaluating the cost effectiveness of pharmaceutical products and other technologies for use within the National Health Service. Based on a content analysis of key documents which shed light on the nature of appraisals, this paper draws attention to the multiple layers of uncertainty and complexity which are latent within the appraisal process, and the often socially constructed mechanisms for tackling these. Epistemic assumptions, bounded rationality and more explicitly relational forms of managing knowledge are applied to this end. These findings are discussed in the context of the literature highlighting the inherently social process of regulation. A framework is developed which posits the various forms of uncertainty, and responses to these, as potential conduits of regulatory bias-in need of further research. That NICE's authority is itself regulated by other actors within the regulatory regime, particularly the pharmaceutical industry, exposes it to the threat of regulatory capture. Following Lehoux, it is concluded that a more transparent and reflexive format for technological appraisals is necessary. This would enable a more robust, defensible form of decision-making and moreover enable NICE to preserve its legitimacy in the midst of pressures which threaten this.

MO-AB-201-01: Regulatory Compliance and Safety with New Radiotherapies: Spheres and Ra-223

DOE Office of Scientific and Technical Information (OSTI.GOV)

Phillips, L.

2015-06-15

The role of the Radiation Safety Officer at a medical facility can be complicated. The complexity of the position is based on the breadth of services provided at the institution and the nature of the radioactive materials license. Medical practices are constantly changing and the use of ionizing radiation continues to rise in this area. Some of the newer medical applications involving radiation have unique regulatory and safety issues that must be addressed. Oversight of the uses of radiation start at the local level (radiation safety officer, radiation safety committee) and are heavily impacted by outside agencies (i.e. Nuclear Regulatorymore » Commission, State Radiologic Health, The Joint Commission (TJC), etc). This session will provide both an overview of regulatory oversight and essential compliance practices as well as practical ways to assess and introduce some of the new applications utilizing radioactive materials into your medical facility. Learning Objectives: Regulatory Compliance and Safety with New Radiotherapies: Spheres and Ra-223 (Lance Phillips) Understand the radioactive materials license amendment process to add new radiotherapies (i.e., SIR-Spheres, Therasphere, Xofigo). Understand the AU approval process for microspheres and Xofigo. Examine the training and handling requirements for new procedures. Understand the process involved with protocol development, SOP in order to define roles and responsibilities. The RSO and The RSC: Challenges and Opportunities (Colin Dimock) Understand how to form an effective Committee. Examine what the Committee does for the Program and the RSO. Understand the importance of Committee engagement. Discuss the balance of the complimentary roles of the RSO and the Committee. The Alphabet Soup of Regulatory Compliance: Being Prepared for Inspections (Linda Kroger) Recognize the various regulatory bodies and organizations with oversight or impact in Nuclear Medicine, Radiology and Radiation Oncology. Examine 10CFR35 requirements as they relate to the everyday practice of Nuclear Medicine and Radiation Oncology. Understand the nature of available guidance documents (e.g., NUREG 1556). Examine the commonalities between TJC and CMS preparedness.« less

Hierarchical Dirichlet process model for gene expression clustering

PubMed Central

2013-01-01

Clustering is an important data processing tool for interpreting microarray data and genomic network inference. In this article, we propose a clustering algorithm based on the hierarchical Dirichlet processes (HDP). The HDP clustering introduces a hierarchical structure in the statistical model which captures the hierarchical features prevalent in biological data such as the gene express data. We develop a Gibbs sampling algorithm based on the Chinese restaurant metaphor for the HDP clustering. We apply the proposed HDP algorithm to both regulatory network segmentation and gene expression clustering. The HDP algorithm is shown to outperform several popular clustering algorithms by revealing the underlying hierarchical structure of the data. For the yeast cell cycle data, we compare the HDP result to the standard result and show that the HDP algorithm provides more information and reduces the unnecessary clustering fragments. PMID:23587447

40 CFR 80.158 - Product transfer documents (PTDs).

Code of Federal Regulations, 2010 CFR

2010-07-01

... exempt base gasoline to be used for research, development, or test purposes only, the following warning must also be stated on the PTD: “For use in research, development, and test programs only.” (6) The...) Use of product codes and other non-regulatory language. (1) Product codes and other non-regulatory...

Scientific, statistical, practical, and regulatory considerations in design space development.

PubMed

Debevec, Veronika; Srčič, Stanko; Horvat, Matej

2018-03-01

The quality by design (QbD) paradigm guides the pharmaceutical industry towards improved understanding of products and processes, and at the same time facilitates a high degree of manufacturing and regulatory flexibility throughout the establishment of the design space. This review article presents scientific, statistical and regulatory considerations in design space development. All key development milestones, starting with planning, selection of factors, experimental execution, data analysis, model development and assessment, verification, and validation, and ending with design space submission, are presented and discussed. The focus is especially on frequently ignored topics, like management of factors and CQAs that will not be included in experimental design, evaluation of risk of failure on design space edges, or modeling scale-up strategy. Moreover, development of a design space that is independent of manufacturing scale is proposed as the preferred approach.

Spatiotemporal transcriptome provides insights into early fruit development of tomato (Solanum lycopersicum).

PubMed

Zhang, Shuaibin; Xu, Meng; Qiu, Zhengkun; Wang, Ketao; Du, Yongchen; Gu, Lianfeng; Cui, Xia

2016-03-18

Early fruit development is crucial for crop production in tomato. After fertilization, the ovary undergoes cell division and cell expansion before maturation. Although the roles of regulatory signals such as hormone and carbohydrate during early fruit development have been studied, the spatial distribution and the sequential initiation of these regulatory signals still need to be explored. Using the tomato cultivar 'Moneymaker', we analyzed the transcriptome of the ovule and the ovary wall/pericarp dissected from four different stages of the early developing fruits by stereoscope. These datasets give us the whole picture about the spatial and temporal signal distribution in early development of ovule and pericarp. Our results indicate that the hormone signal was initiated in both ovule and pericarp after fertilization. After that, different signals were activated in ovule and pericarp due to their distinct developmental processes. Our study provides spatiotemporal regulatory landscape of gene expression with sequential information which was not studied by previous work and further strengthens the comprehension of the regulatory and metabolic events controlling early fruit development.

A tutorial for developing a topical cream formulation based on the Quality by Design approach.

PubMed

Simões, Ana; Veiga, Francisco; Vitorino, Carla; Figueiras, Ana

2018-06-20

The pharmaceutical industry has entered in a new era, as there is a growing interest in increasing the quality standards of dosage forms, through the implementation of more structured development and manufacturing approaches. For many decades, the manufacturing of drug products was controlled by a regulatory framework to guarantee the quality of the final product through a fixed process and exhaustive testing. Limitations related to the Quality by Test (QbT) system have been widely acknowledged. The emergence of Quality by Design (QbD) as a systematic and risk-based approach introduced a new quality concept based on a good understanding of how raw materials and process parameters influence the final quality profile. Although the QbD system has been recognized as a revolutionary approach to product development and manufacturing, its full implementation in the pharmaceutical field is still limited. This is particularly evident in the case of semisolid complex formulation development. The present review aims at establishing a practical QbD framework to describe all stages comprised in the pharmaceutical development of a conventional cream in a comprehensible manner. Copyright © 2018. Published by Elsevier Inc.

An Approach for Implementation of Project Management Information Systems

NASA Astrophysics Data System (ADS)

Běrziša, Solvita; Grabis, Jānis

Project management is governed by project management methodologies, standards, and other regulatory requirements. This chapter proposes an approach for implementing and configuring project management information systems according to requirements defined by these methodologies. The approach uses a project management specification framework to describe project management methodologies in a standardized manner. This specification is used to automatically configure the project management information system by applying appropriate transformation mechanisms. Development of the standardized framework is based on analysis of typical project management concepts and process and existing XML-based representations of project management. A demonstration example of project management information system's configuration is provided.

Translating New Science Into the Drug Review Process

PubMed Central

Rouse, Rodney; Kruhlak, Naomi; Weaver, James; Burkhart, Keith; Patel, Vikram; Strauss, David G.

2017-01-01

In 2011, the US Food and drug Administration (FDA) developed a strategic plan for regulatory science that focuses on developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of FDA-regulated products. In line with this, the Division of Applied Regulatory Science was created to move new science into the Center for Drug Evaluation and Research (CDER) review process and close the gap between scientific innovation and drug review. The Division, located in the Office of Clinical Pharmacology, is unique in that it performs mission-critical applied research and review across the translational research spectrum including in vitro and in vivo laboratory research, in silico computational modeling and informatics, and integrated clinical research covering clinical pharmacology, experimental medicine, and postmarket analyses. The Division collaborates with Offices throughout CDER, across the FDA, other government agencies, academia, and industry. The Division is able to rapidly form interdisciplinary teams of pharmacologists, biologists, chemists, computational scientists, and clinicians to respond to challenging regulatory questions for specific review issues and for longer-range projects requiring the development of predictive models, tools, and biomarkers to speed the development and regulatory evaluation of safe and effective drugs. This article reviews the Division’s recent work and future directions, highlighting development and validation of biomarkers; novel humanized animal models; translational predictive safety combining in vitro, in silico, and in vivo clinical biomarkers; chemical and biomedical informatics tools for safety predictions; novel approaches to speed the development of complex generic drugs, biosimilars, and antibiotics; and precision medicine. PMID:29568713

Transcriptomic changes during maize roots development responsive to Cadmium (Cd) pollution using comparative RNAseq-based approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peng, Hua; Sichuan Tourism College, Chengdu, 610000, Sichuan; He, Xiujing

The heavy metal cadmium (Cd), acts as a widespread environmental contaminant, which has shown to adversely affect human health, food safety and ecosystem safety in recent years. However, research on how plant respond to various kinds of heavy metal stress is scarcely reported, especially for understanding of complex molecular regulatory mechanisms and elucidating the gene networks of plant respond to Cd stress. Here, transcriptomic changes during Mo17 and B73 seedlings development responsive to Cd pollution were investigated and comparative RNAseq-based approach in both genotypes were performed. 115 differential expression genes (DEGs) with significant alteration in expression were found co-modulated inmore » both genotypes during the maize seedling development; of those, most of DGEs were found comprised of stress and defense responses proteins, transporters, as well as transcription factors, such as thaumatin-like protein, ZmOPR2 and ZmOPR5. More interestingly, genotype-specific transcriptional factors changes induced by Cd stress were found contributed to the regulatory mechanism of Cd sensitivity in both different genotypes. Moreover, 12 co-expression modules associated with specific biological processes or pathways (M1 to M12) were identified by consensus co-expression network. These results will expand our understanding of complex molecular mechanism of response and defense to Cd exposure in maize seedling roots. - Highlights: • Transcriptomic changes responsive to Cd pollution using comparative RNAseq-based approach. • 115 differential expression genes (DEGs) were found co-modulated in both genotypes. • Most of DGEs belong to stress and defense responses proteins, transporters, transcription factors. • 12 co-expression modules associated with specific biological processes or pathways. • Genotype-specific transcriptional factors changes induced by Cd stress were found.« less

CoryneRegNet: an ontology-based data warehouse of corynebacterial transcription factors and regulatory networks.

PubMed

Baumbach, Jan; Brinkrolf, Karina; Czaja, Lisa F; Rahmann, Sven; Tauch, Andreas

2006-02-14

The application of DNA microarray technology in post-genomic analysis of bacterial genome sequences has allowed the generation of huge amounts of data related to regulatory networks. This data along with literature-derived knowledge on regulation of gene expression has opened the way for genome-wide reconstruction of transcriptional regulatory networks. These large-scale reconstructions can be converted into in silico models of bacterial cells that allow a systematic analysis of network behavior in response to changing environmental conditions. CoryneRegNet was designed to facilitate the genome-wide reconstruction of transcriptional regulatory networks of corynebacteria relevant in biotechnology and human medicine. During the import and integration process of data derived from experimental studies or literature knowledge CoryneRegNet generates links to genome annotations, to identified transcription factors and to the corresponding cis-regulatory elements. CoryneRegNet is based on a multi-layered, hierarchical and modular concept of transcriptional regulation and was implemented by using the relational database management system MySQL and an ontology-based data structure. Reconstructed regulatory networks can be visualized by using the yFiles JAVA graph library. As an application example of CoryneRegNet, we have reconstructed the global transcriptional regulation of a cellular module involved in SOS and stress response of corynebacteria. CoryneRegNet is an ontology-based data warehouse that allows a pertinent data management of regulatory interactions along with the genome-scale reconstruction of transcriptional regulatory networks. These models can further be combined with metabolic networks to build integrated models of cellular function including both metabolism and its transcriptional regulation.

Data Integrity-A Study of Current Regulatory Thinking and Action.

PubMed

Shafiei, Nader; De Montardy, Regis; Rivera-Martinez, Edwin

2015-01-01

In reaction to breaches of data integrity in the pharmaceutical industry, regulatory authorities have introduced inspection approaches or initiatives with the aim of reducing occurrences of data integrity problems. This review article-based on study of 65 cases of regulatory action from 2002 to 2014-provides an overview of current regulatory thinking and action on breaches of data integrity affecting GxP (health-related regulations) processes supporting non-clinical studies, clinical studies, laboratory controls, and production controls. These case studies largely represent position of the U.S. Food and Drug Administration and the regulatory agencies affiliated with the European Medicines Agency. Also discussed is the role of human factors as a potential source of data integrity problems. The article concludes by recommending some remedial controls that could be established to avoid or reduce occurrences of data integrity problems.Lay Abstract: In fulfilling their mission to protect public health, regulatory agencies (e.g., U.S. Food and Drug Administration, European Medicines Agency) must establish confidence that medical products they approve are fit for their intended use. In so doing they rely on scientific and operational data generated during research, development, manufacturing, sales, marketing, distribution, and post-marketing surveillance activities. The level of confidence they build is directly proportional to the scientific validity and integrity of data presented to them by the sponsors of medical products. In this article we present analysis of 65 case studies that document regulatory action taken by various regulatory agencies on breach of data integrity between 2002 and 2014. The ensuing discussion on current trends largely represents position of the U.S. Food and Drug Administration and European Medicines Agency. The article concludes by proposing some remedial controls that could be established by pharmaceutical companies to avoid or reduce occurrences of data integrity problems. © PDA, Inc. 2015.

The Regulatory Review Process in South Africa: Challenges and Opportunities for a New Improved System.

PubMed

Keyter, Andrea; Gouws, Joey; Salek, Sam; Walker, Stuart

2018-01-01

The aims of this study were to assess the regulatory review process in South Africa from 2015 to 2017, identify the key milestones and timelines; evaluate the effectiveness of measures to ensure consistency, transparency, timeliness, and predictability in the review process; and to provide recommendations for enhanced regulatory practices. A questionnaire was completed by the Medicines Control Council (MCC) to describe the organization of the authority, record key milestones and timelines in the review process and to identify good review practices (GRevPs). Currently, the MCC conducts a full assessment of quality, efficacy, and safety data in the review of all applications. The overall regulatory median approval time decreased by 14% in 2017 (1411 calendar days) compared with that of 2016, despite the 27% increase in the number of applications. However, the MCC has no target for overall approval time of new active substance applications and no targets for key review milestones. Guidelines, standard operating procedures, and review templates are in place, while the formal implementation of GRevPs and the application of an electronic document management system are planned for the near future. As the MCC transitions to the newly established South Africa Health Products Regulatory Authority, it would be crucial for the authority to recognize the opportunities for an enhanced regulatory review and should consider models such as abridged assessment, which encompass elements of risk stratification and reliance. It is hoped that resource constraints may then be alleviated and capacity developed to meet target timelines.

Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution.

PubMed

Vierstra, Jeff; Rynes, Eric; Sandstrom, Richard; Zhang, Miaohua; Canfield, Theresa; Hansen, R Scott; Stehling-Sun, Sandra; Sabo, Peter J; Byron, Rachel; Humbert, Richard; Thurman, Robert E; Johnson, Audra K; Vong, Shinny; Lee, Kristen; Bates, Daniel; Neri, Fidencio; Diegel, Morgan; Giste, Erika; Haugen, Eric; Dunn, Douglas; Wilken, Matthew S; Josefowicz, Steven; Samstein, Robert; Chang, Kai-Hsin; Eichler, Evan E; De Bruijn, Marella; Reh, Thomas A; Skoultchi, Arthur; Rudensky, Alexander; Orkin, Stuart H; Papayannopoulou, Thalia; Treuting, Piper M; Selleri, Licia; Kaul, Rajinder; Groudine, Mark; Bender, M A; Stamatoyannopoulos, John A

2014-11-21

To study the evolutionary dynamics of regulatory DNA, we mapped >1.3 million deoxyribonuclease I-hypersensitive sites (DHSs) in 45 mouse cell and tissue types, and systematically compared these with human DHS maps from orthologous compartments. We found that the mouse and human genomes have undergone extensive cis-regulatory rewiring that combines branch-specific evolutionary innovation and loss with widespread repurposing of conserved DHSs to alternative cell fates, and that this process is mediated by turnover of transcription factor (TF) recognition elements. Despite pervasive evolutionary remodeling of the location and content of individual cis-regulatory regions, within orthologous mouse and human cell types the global fraction of regulatory DNA bases encoding recognition sites for each TF has been strictly conserved. Our findings provide new insights into the evolutionary forces shaping mammalian regulatory DNA landscapes. Copyright © 2014, American Association for the Advancement of Science.

Identifying significant genetic regulatory networks in the prostate cancer from microarray data based on transcription factor analysis and conditional independency

PubMed Central

2009-01-01

Background Prostate cancer is a world wide leading cancer and it is characterized by its aggressive metastasis. According to the clinical heterogeneity, prostate cancer displays different stages and grades related to the aggressive metastasis disease. Although numerous studies used microarray analysis and traditional clustering method to identify the individual genes during the disease processes, the important gene regulations remain unclear. We present a computational method for inferring genetic regulatory networks from micorarray data automatically with transcription factor analysis and conditional independence testing to explore the potential significant gene regulatory networks that are correlated with cancer, tumor grade and stage in the prostate cancer. Results To deal with missing values in microarray data, we used a K-nearest-neighbors (KNN) algorithm to determine the precise expression values. We applied web services technology to wrap the bioinformatics toolkits and databases to automatically extract the promoter regions of DNA sequences and predicted the transcription factors that regulate the gene expressions. We adopt the microarray datasets consists of 62 primary tumors, 41 normal prostate tissues from Stanford Microarray Database (SMD) as a target dataset to evaluate our method. The predicted results showed that the possible biomarker genes related to cancer and denoted the androgen functions and processes may be in the development of the prostate cancer and promote the cell death in cell cycle. Our predicted results showed that sub-networks of genes SREBF1, STAT6 and PBX1 are strongly related to a high extent while ETS transcription factors ELK1, JUN and EGR2 are related to a low extent. Gene SLC22A3 may explain clinically the differentiation associated with the high grade cancer compared with low grade cancer. Enhancer of Zeste Homolg 2 (EZH2) regulated by RUNX1 and STAT3 is correlated to the pathological stage. Conclusions We provide a computational framework to reconstruct the genetic regulatory network from the microarray data using biological knowledge and constraint-based inferences. Our method is helpful in verifying possible interaction relations in gene regulatory networks and filtering out incorrect relations inferred by imperfect methods. We predicted not only individual gene related to cancer but also discovered significant gene regulation networks. Our method is also validated in several enriched published papers and databases and the significant gene regulatory networks perform critical biological functions and processes including cell adhesion molecules, androgen and estrogen metabolism, smooth muscle contraction, and GO-annotated processes. Those significant gene regulations and the critical concept of tumor progression are useful to understand cancer biology and disease treatment. PMID:20025723

Metabolic Engineering for Substrate Co-utilization

NASA Astrophysics Data System (ADS)

Gawand, Pratish

Production of biofuels and bio-based chemicals is being increasingly pursued by chemical industry to reduce its dependence on petroleum. Lignocellulosic biomass (LCB) is an abundant source of sugars that can be used for producing biofuels and bio-based chemicals using fermentation. Hydrolysis of LCB results in a mixture of sugars mainly composed of glucose and xylose. Fermentation of such a sugar mixture presents multiple technical challenges at industrial scale. Most industrial microorganisms utilize sugars in a sequential manner due to the regulatory phenomenon of carbon catabolite repression (CCR). Due to sequential utilization of sugars, the LCB-based fermentation processes suffer low productivities and complicated operation. Performance of fermentation processes can be improved by metabolic engineering of microorganisms to obtain superior characteristics such as high product yield. With increased computational power and availability of complete genomes of microorganisms, use of model-based metabolic engineering is now a common practice. The problem of sequential sugar utilization, however, is a regulatory problem, and metabolic models have never been used to solve such regulatory problems. The focus of this thesis is to use model-guided metabolic engineering to construct industrial strains capable of co-utilizing sugars. First, we develop a novel bilevel optimization algorithm SimUp, that uses metabolic models to identify reaction deletion strategies to force co-utilization of two sugars. We then use SimUp to identify reaction deletion strategies to force glucose-xylose co-utilization in Escherichia coli. To validate SimUp predictions, we construct three mutants with multiple gene knockouts and test them for glucose-xylose utilization characteristics. Two mutants, designated as LMSE2 and LMSE5, are shown to co-utilize glucose and xylose in agreement with SimUp predictions. To understand the molecular mechanism involved in glucose-xylose co-utilization of the mutant LMSE2, the mutant is subjected to targeted and whole genome sequencing. Finally, we use the mutant LMSE2 to produce D-ribose from a mixture of glucose and xylose by overexpressing an endogenous phosphatase. The methods developed in this thesis are anticipated to provide a novel approach to solve sugar co-utilization problem in industrial microorganisms, and provide insights into microbial response to forced co-utilization of sugars.

Revealing cell cycle control by combining model-based detection of periodic expression with novel cis-regulatory descriptors

PubMed Central

Andersson, Claes R; Hvidsten, Torgeir R; Isaksson, Anders; Gustafsson, Mats G; Komorowski, Jan

2007-01-01

Background We address the issue of explaining the presence or absence of phase-specific transcription in budding yeast cultures under different conditions. To this end we use a model-based detector of gene expression periodicity to divide genes into classes depending on their behavior in experiments using different synchronization methods. While computational inference of gene regulatory circuits typically relies on expression similarity (clustering) in order to find classes of potentially co-regulated genes, this method instead takes advantage of known time profile signatures related to the studied process. Results We explain the regulatory mechanisms of the inferred periodic classes with cis-regulatory descriptors that combine upstream sequence motifs with experimentally determined binding of transcription factors. By systematic statistical analysis we show that periodic classes are best explained by combinations of descriptors rather than single descriptors, and that different combinations correspond to periodic expression in different classes. We also find evidence for additive regulation in that the combinations of cis-regulatory descriptors associated with genes periodically expressed in fewer conditions are frequently subsets of combinations associated with genes periodically expression in more conditions. Finally, we demonstrate that our approach retrieves combinations that are more specific towards known cell-cycle related regulators than the frequently used clustering approach. Conclusion The results illustrate how a model-based approach to expression analysis may be particularly well suited to detect biologically relevant mechanisms. Our new approach makes it possible to provide more refined hypotheses about regulatory mechanisms of the cell cycle and it can easily be adjusted to reveal regulation of other, non-periodic, cellular processes. PMID:17939860

In silico analysis of cis-acting regulatory elements in 5' regulatory regions of sucrose transporter gene families in rice (Oryza sativa Japonica) and Arabidopsis thaliana.

PubMed

Ibraheem, Omodele; Botha, Christiaan E J; Bradley, Graeme

2010-12-01

The regulation of gene expression involves a multifarious regulatory system. Each gene contains a unique combination of cis-acting regulatory sequence elements in the 5' regulatory region that determines its temporal and spatial expression. Cis-acting regulatory elements are essential transcriptional gene regulatory units; they control many biological processes and stress responses. Thus a full understanding of the transcriptional gene regulation system will depend on successful functional analyses of cis-acting elements. Cis-acting regulatory elements present within the 5' regulatory region of the sucrose transporter gene families in rice (Oryza sativa Japonica cultivar-group) and Arabidopsis thaliana, were identified using a bioinformatics approach. The possible cis-acting regulatory elements were predicted by scanning 1.5kbp of 5' regulatory regions of the sucrose transporter genes translational start sites, using Plant CARE, PLACE and Genomatix Matinspector professional databases. Several cis-acting regulatory elements that are associated with plant development, plant hormonal regulation and stress response were identified, and were present in varying frequencies within the 1.5kbp of 5' regulatory region, among which are; A-box, RY, CAT, Pyrimidine-box, Sucrose-box, ABRE, ARF, ERE, GARE, Me-JA, ARE, DRE, GA-motif, GATA, GT-1, MYC, MYB, W-box, and I-box. This result reveals the probable cis-acting regulatory elements that possibly are involved in the expression and regulation of sucrose transporter gene families in rice and Arabidopsis thaliana during cellular development or environmental stress conditions. Copyright © 2010 Elsevier Ltd. All rights reserved.

Parallel comparative proteomics and phosphoproteomics reveal that cattle myostatin regulates phosphorylation of key enzymes in glycogen metabolism and glycolysis pathway

PubMed Central

Yang, Shuping; Li, Xin; Liu, Xinfeng; Ding, Xiangbin; Xin, Xiangbo; Jin, Congfei; Zhang, Sheng; Li, Guangpeng; Guo, Hong

2018-01-01

MSTN-encoded myostatin is a negative regulator of skeletal muscle development. Here, we utilized the gluteus tissues from MSTN gene editing and wild type Luxi beef cattle which are native breed of cattle in China, performed tandem mass tag (TMT) -based comparative proteomics and phosphoproteomics analyses to investigate the regulatory mechanism of MSTN related to cellular metabolism and signaling pathway in muscle development. Out of 1,315 proteins, 69 differentially expressed proteins (DEPs) were found in global proteomics analysis. Meanwhile, 149 differentially changed phosphopeptides corresponding to 76 unique phosphorylated proteins (DEPPs) were detected from 2,600 identified phosphopeptides in 702 phosphorylated proteins. Bioinformatics analyses suggested that majority of DEPs and DEPPs were closely related to glycolysis, glycogenolysis, and muscle contractile fibre processes. The global discovery results were validated by Multiple Reaction Monitoring (MRM)-based targeted peptide quantitation analysis, western blotting, and muscle glycogen content measurement. Our data revealed that increase in abundance of key enzymes and phosphorylation on their regulatory sites appears responsible for the enhanced glycogenolysis and glycolysis in MSTN−/−. The elevated glycogenolysis was assocaited with an enhanced phosphorylation of Ser1018 in PHKA1, and Ser641/Ser645 in GYS1, which were regulated by upstream phosphorylated AKT-GSK3β pathway and highly consistent with the lower glycogen content in gluteus of MSTN−/−. Collectively, this study provides new insights into the regulatory mechanisms of MSTN involved in energy metabolism and muscle growth. PMID:29541418

Introduction of Building Information Modeling (BIM) Technologies in Construction

NASA Astrophysics Data System (ADS)

Milyutina, M. A.

2018-05-01

The issues of introduction of building information modeling (BIM) in construction industry are considered in this work. The advantages of this approach and perspectives of the transition to new design technologies, construction process management, and operation in the near future are stated. The importance of development of pilot projects that should identify the ways and means of verification of the regulatory and technical base, as well as economic indicators in the transition to Building Information Technologies in the construction, is noted.

Environmental Assessment Addressing the Defense Language Institute English Language Center (DLIELC), and the Inter-American Air Forces Academy (IAAFA) Area Development Plan at Lackland Air Force Base, Texas

DTIC Science & Technology

2012-01-01

Heat island” refers to built up areas that have hotter surface and air temperatures than nearby rural areas. Heat island effect occurs when...Summary of Environmental Effects The public and regulatory agency scoping process focused the analysis on the following environmental resources... effects of implementing the DLIELC and IAAFA ADP are not significant, that preparation of an Environmental Impact Statement is unnecessary, and that a

Development and technology transfer of Haemophilus influenzae type b conjugate vaccines for developing countries.

PubMed

Beurret, Michel; Hamidi, Ahd; Kreeftenberg, Hans

2012-07-13

This paper describes the development of a Haemophilus influenzae type b (Hib) conjugate vaccine at the National Institute for Public Health and the Environment/Netherlands Vaccine Institute (RIVM/NVI, Bilthoven, The Netherlands), and the subsequent transfer of its production process to manufacturers in developing countries. In 1998, at the outset of the project, the majority of the world's children were not immunized against Hib because of the high price and limited supply of the conjugate vaccines, due partly to the fact that local manufacturers in developing countries did not master the Hib conjugate production technology. To address this problem, the RIVM/NVI has developed a robust Hib conjugate vaccine production process based on a proven model, and transferred this technology to several partners in India, Indonesia, Korea and China. As a result, emerging manufacturers in developing countries acquired modern technologies previously unavailable to them. This has in turn facilitated their approach to producing other conjugate vaccines. As an additional spin-off from the project, a World Health Organization (WHO) Hib quality control (QC) course was designed and conducted at the RIVM/NVI, resulting in an increased regulatory capacity for conjugate vaccines in developing countries at the National Regulatory Authority (NRA) level. For the local populations, this has translated into an increased and sustainable supply of affordable Hib conjugate-containing combination vaccines. During the course of this project, developing countries have demonstrated their ability to produce large quantities of high-quality modern vaccines after a successful transfer of the technology. Copyright © 2012 Elsevier Ltd. All rights reserved.

A primer on thermodynamic-based models for deciphering transcriptional regulatory logic.

PubMed

Dresch, Jacqueline M; Richards, Megan; Ay, Ahmet

2013-09-01

A rigorous analysis of transcriptional regulation at the DNA level is crucial to the understanding of many biological systems. Mathematical modeling has offered researchers a new approach to understanding this central process. In particular, thermodynamic-based modeling represents the most biophysically informed approach aimed at connecting DNA level regulatory sequences to the expression of specific genes. The goal of this review is to give biologists a thorough description of the steps involved in building, analyzing, and implementing a thermodynamic-based model of transcriptional regulation. The data requirements for this modeling approach are described, the derivation for a specific regulatory region is shown, and the challenges and future directions for the quantitative modeling of gene regulation are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

Deep Reinforcement Learning of Cell Movement in the Early Stage of C. elegans Embryogenesis.

PubMed

Wang, Zi; Wang, Dali; Li, Chengcheng; Xu, Yichi; Li, Husheng; Bao, Zhirong

2018-04-25

Cell movement in the early phase of C. elegans development is regulated by a highly complex process in which a set of rules and connections are formulated at distinct scales. Previous efforts have demonstrated that agent-based, multi-scale modeling systems can integrate physical and biological rules and provide new avenues to study developmental systems. However, the application of these systems to model cell movement is still challenging and requires a comprehensive understanding of regulatory networks at the right scales. Recent developments in deep learning and reinforcement learning provide an unprecedented opportunity to explore cell movement using 3D time-lapse microscopy images. We present a deep reinforcement learning approach within an agent-based modeling system to characterize cell movement in the embryonic development of C. elegans. Our modeling system captures the complexity of cell movement patterns in the embryo and overcomes the local optimization problem encountered by traditional rule-based, agent-based modeling that uses greedy algorithms. We tested our model with two real developmental processes: the anterior movement of the Cpaaa cell via intercalation and the rearrangement of the superficial left-right asymmetry. In the first case, the model results suggested that Cpaaa's intercalation is an active directional cell movement caused by the continuous effects from a longer distance (farther than the length of two adjacent cells), as opposed to a passive movement caused by neighbor cell movements. In the second case, a leader-follower mechanism well explained the collective cell movement pattern in the asymmetry rearrangement. These results showed that our approach to introduce deep reinforcement learning into agent-based modeling can test regulatory mechanisms by exploring cell migration paths in a reverse engineering perspective. This model opens new doors to explore the large datasets generated by live imaging. Source code is available at https://github.com/zwang84/drl4cellmovement. dwang7@utk.edu, baoz@mskcc.org. Supplementary data are available at Bioinformatics online.

75 FR 41562 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving a...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-16

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-62482; File No. SR-FINRA-2010-024] Self...) and FINRA Rule 4230 (Required Submissions for Requests for Extensions of Time Under Regulation T and... Regulation T and SEC Rule 15c3-3) as part of the process of developing a consolidated FINRA rulebook. The...

75 FR 8770 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-25

... Change To Repeal Incorporated NYSE Rule 405(4) (Common Sales Accounts) February 18, 2010. Pursuant to...) (Common Sales Accounts) as part of the process to develop the consolidated FINRA rulebook. The text of the... NYSE Rule 405(4) (Common Sales Accounts).\\4\\ \\3\\ The current FINRA rulebook consists of (1) FINRA Rules...

Facilitating a More Efficient Commercial Review Process for Pediatric Drugs and Biologics

PubMed Central

Rykhus, Ryan D.; Shepard, Zachary V.; Young, Alix; Frisby, Hadley; Calder, Kailee A.; Coon, Collin M.; Falk, Justin A.; McAndrews, Sydney R.; Turner, Aspen; Chang, Christina; Michelsohn, Johanna; Petch, Raegan; Dieker, Sarah M.; Markworth, Benjamin H.; Alamo-Perez, Kevin; Hosack, Aaron J.; Berg, Jacob M.; Schmidt, Christian; Storsberg, Joachim; Brown, Mark A.

Over the past two decades, the biopharmaceutical industry has seen unprecedented expansion and innovation in concert with significant technological advancements. While the industry has experienced marked growth, the regulatory system in the United States still operates at a capacity much lower than the influx of new drug and biologic candidates. As a result, it has become standard for months or even years of waiting for commercial approval by the U.S. Food and Drug Administration. These regulatory delays have generated a system that stifles growth and innovation due to the exorbitant costs associated with awaiting approval from the nation’s sole regulatory agency. The recent re-emergence of diseases that impact pediatric demographics represents one particularly acute reason for developing a regulatory system that facilitates a more efficient commercial review process. Herein, we present a range of initiatives that could represent early steps toward alleviating the delays in approving life-saving therapeutics. PMID:29271878

Regulating transgenic crops sensibly: lessons from plant breeding, biotechnology and genomics.

PubMed

Bradford, Kent J; Van Deynze, Allen; Gutterson, Neal; Parrott, Wayne; Strauss, Steven H

2005-04-01

The costs of meeting regulatory requirements and market restrictions guided by regulatory criteria are substantial impediments to the commercialization of transgenic crops. Although a cautious approach may have been prudent initially, we argue that some regulatory requirements can now be modified to reduce costs and uncertainty without compromising safety. Long-accepted plant breeding methods for incorporating new diversity into crop varieties, experience from two decades of research on and commercialization of transgenic crops, and expanding knowledge of plant genome structure and dynamics all indicate that if a gene or trait is safe, the genetic engineering process itself presents little potential for unexpected consequences that would not be identified or eliminated in the variety development process before commercialization. We propose that as in conventional breeding, regulatory emphasis should be on phenotypic rather than genomic characteristics once a gene or trait has been shown to be safe.

Investigating the state of physiologically based kinetic modelling practices and challenges associated with gaining regulatory acceptance of model applications.

PubMed

Paini, Alicia; Leonard, Jeremy A; Kliment, Tomas; Tan, Yu-Mei; Worth, Andrew

2017-11-01

Physiologically based kinetic (PBK) models are used widely throughout a number of working sectors, including academia and industry, to provide insight into the dosimetry related to observed adverse health effects in humans and other species. Use of these models has increased over the last several decades, especially in conjunction with emerging alternative methods to animal testing, such as in vitro studies and data-driven in silico quantitative-structure-activity-relationship (QSAR) predictions. Experimental information derived from these new approach methods can be used as input for model parameters and allows for increased confidence in models for chemicals that did not have in vivo data for model calibration. Despite significant advancements in good modelling practice (GMP) for model development and evaluation, there remains some reluctance among regulatory agencies to use such models during the risk assessment process. Here, the results of a survey disseminated to the modelling community are presented in order to inform the frequency of use and applications of PBK models in science and regulatory submission. Additionally, the survey was designed to identify a network of investigators involved in PBK modelling and knowledgeable of GMP so that they might be contacted in the future for peer review of PBK models, especially in regards to vetting the models to such a degree as to gain a greater acceptance for regulatory purposes. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Regulatory immune cells in regulation of intestinal inflammatory response to microbiota

PubMed Central

Cong, Y; Liu, Z

2015-01-01

The intestinal lumen harbors nearly 100 trillion commensal bacteria that exert crucial function for health. An elaborate balance between immune responses and tolerance to intestinal microbiota is required to maintain intestinal homeostasis. This process depends on diverse regulatory mechanisms, including both innate and adaptive immunity. Dysregulation of the homeostasis between intestinal immune systems and microbiota has been shown to be associated with the development of inflammatory bowel diseases (IBD) in genetically susceptible populations. In this review, we discuss the recent progress reported in studies of distinct types of regulatory immune cells in the gut, including intestinal intraepithelial lymphocytes, Foxp3+ regulatory T cells, regulatory B cells, alternatively activated macrophages, dendritic cells, and innate lymphoid cells, and how dysfunction of this immune regulatory system contributes to intestinal diseases such as IBD. Moreover, we discuss the manipulation of these regulatory immune cells as a potential therapeutic method for management of intestinal inflammatory disorders. PMID:26080708

Regulatory immune cells in regulation of intestinal inflammatory response to microbiota.

PubMed

Sun, M; He, C; Cong, Y; Liu, Z

2015-09-01

The intestinal lumen harbors nearly 100 trillion commensal bacteria that exert crucial function for health. An elaborate balance between immune responses and tolerance to intestinal microbiota is required to maintain intestinal homeostasis. This process depends on diverse regulatory mechanisms, including both innate and adaptive immunity. Dysregulation of the homeostasis between intestinal immune systems and microbiota has been shown to be associated with the development of inflammatory bowel diseases (IBD) in genetically susceptible populations. In this review, we discuss the recent progress reported in studies of distinct types of regulatory immune cells in the gut, including intestinal intraepithelial lymphocytes, Foxp3(+) regulatory T cells, regulatory B cells, alternatively activated macrophages, dendritic cells, and innate lymphoid cells, and how dysfunction of this immune regulatory system contributes to intestinal diseases such as IBD. Moreover, we discuss the manipulation of these regulatory immune cells as a potential therapeutic method for management of intestinal inflammatory disorders.

Implementation of the NANoREG Safe-by-Design approach for different nanomaterial applications

NASA Astrophysics Data System (ADS)

Micheletti, C.; Roman, M.; Tedesco, E.; Olivato, I.; Benetti, F.

2017-06-01

The Safe-by-Design (SbD) concept is already in use in different industrial sectors as an integral part of the innovation process management. However, the adopted approach is often limited to design solutions aiming at hazard reduction. Safety is not always considered during the innovation process, mainly due to the lack of knowledge (e.g. in small and medium companies, SMEs) and the lack of dialogue between actors along the innovation chain. The net result is that safety is considered only at the end of the innovation process at the market authorization phase, with potential loss of time and money. This is especially valid for manufactured nanomaterials (MNM) for which the regulatory context is not completely developed, and the safety knowledge is not readily available. In order to contribute to a sustainable innovation process in the nanotechnology field by maximising both benefits and safety, the NANoREG project developed a Safe Innovation approach, based on two elements: the Safe-by-Design approach which aims at including risk assessment into all innovation stages; and the Regulatory Preparedness, focused on the dialogue with stakeholders along the innovation chain. In this work we present some examples about the implementation in our Laboratory of this approach for different MNM applications, covering different steps of the innovation chain. The case studies include: the feasibility study of a medical device including substances, for topical application; the testing of two potential nanotech solutions for the consolidation of cultural heritage artifacts; the testing of coatings already on the market for other uses, which was tested as food contact materials (FCM) to evaluate the conformity to food applications. These three examples represent a good opportunity to show the importance of NANoREG SbD and Safe Innovation Approach in general, for developing new nanotechnology-based products, also highlighting the crucial role of EU ProSafe project in promoting this concept to industries and interested stakeholders.

Manufacturing human mesenchymal stem cells at clinical scale: process and regulatory challenges.

PubMed

Jossen, Valentin; van den Bos, Christian; Eibl, Regine; Eibl, Dieter

2018-05-01

Human mesenchymal stem cell (hMSC)-based therapies are of increasing interest in the field of regenerative medicine. As economic considerations have shown, allogeneic therapy seems to be the most cost-effective method. Standardized procedures based on instrumented single-use bioreactors have been shown to provide billion of cells with consistent product quality and to be superior to traditional expansions in planar cultivation systems. Furthermore, under consideration of the complex nature and requirements of allogeneic hMSC-therapeutics, a new equipment for downstream processing (DSP) was successfully evaluated. This mini-review summarizes both the current state of the hMSC production process and the challenges which have to be taken into account when efficiently producing hMSCs for the clinical scale. Special emphasis is placed on the upstream processing (USP) and DSP operations which cover expansion, harvesting, detachment, separation, washing and concentration steps, and the regulatory demands.

Functional food and nutraceutical registration processes in Japan and China: a diffusion of innovation perspective.

PubMed

Patel, Darshika; Dufour, Yvon; Domigan, Neil

2008-01-01

Purpose - This paper looks into the functional food and nutraceutical registration processes in Japan and China. The Japanese have developed the Foods for Specified Health Use (FOSHU) registration process whereas the Chinese have put into place the Health Food (HF) registration process. The aim of this paper is to compare the regulation processes between the two countries in search for answers to three core empirical questions: (1) how have the registration processes developed and changed? (2) What are the similarities and differences between the processes of registration in the two countries investigated? (3) Why are the registration processes similar/different? Method - The study was conducted using secondary sources. The literature surveyed covered academic journals, trade journals, magazine and newspaper articles, market reports, proceedings, books and web pages of relevant regulatory authorities and regulatory consultants. Information from the more recently published sources was used preferentially over older sources. As well as using the most recent sources, information was selected on the basis of which source it was from. Official regulations and SFDA and MHLW websites would contain accurate and up to date information and information from here would be taken as true over other sources of information. Results - The two diagrams of the registration processes respectively in Japan and China clearly show that there are similarities and differences. There are six categories under which these can be found: (1) the scientific evidence required; (2) the application process; (3) the evaluation process; (4) the law and the categories of products; (5) the labels and the types of claims; and finally (6) the cost and the time involved. Conclusions -The data analysis suggests that the process of diffusion of innovation played a role in the development of the regulations. Further it was found that while Japan was at the outset a pioneer innovator in nutraceutical registration processes, there are indications that in more recent years it too imitated other countries. NOVELTY STATEMENT: The assortment of regulatory regimes creates much uncertainty for the firms and the lack of familiarity and poor knowledge of the regulatory situation increases the risk of failure. The research presented in this paper provides highly valuable information to any biotech/pharmaceutical/nutraceutical companies developing their market entry strategy in Japan and China. There are few national and international studies of drug registration application processes but even fewer comparative studies of functional food and neutraceutical registration application processes such as this one and none using a diffusion of innovation perspective.

Process development of a New Haemophilus influenzae type b conjugate vaccine and the use of mathematical modeling to identify process optimization possibilities.

PubMed

Hamidi, Ahd; Kreeftenberg, Hans; V D Pol, Leo; Ghimire, Saroj; V D Wielen, Luuk A M; Ottens, Marcel

2016-05-01

Vaccination is one of the most successful public health interventions being a cost-effective tool in preventing deaths among young children. The earliest vaccines were developed following empirical methods, creating vaccines by trial and error. New process development tools, for example mathematical modeling, as well as new regulatory initiatives requiring better understanding of both the product and the process are being applied to well-characterized biopharmaceuticals (for example recombinant proteins). The vaccine industry is still running behind in comparison to these industries. A production process for a new Haemophilus influenzae type b (Hib) conjugate vaccine, including related quality control (QC) tests, was developed and transferred to a number of emerging vaccine manufacturers. This contributed to a sustainable global supply of affordable Hib conjugate vaccines, as illustrated by the market launch of the first Hib vaccine based on this technology in 2007 and concomitant price reduction of Hib vaccines. This paper describes the development approach followed for this Hib conjugate vaccine as well as the mathematical modeling tool applied recently in order to indicate options for further improvements of the initial Hib process. The strategy followed during the process development of this Hib conjugate vaccine was a targeted and integrated approach based on prior knowledge and experience with similar products using multi-disciplinary expertise. Mathematical modeling was used to develop a predictive model for the initial Hib process (the 'baseline' model) as well as an 'optimized' model, by proposing a number of process changes which could lead to further reduction in price. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:568-580, 2016. © 2016 American Institute of Chemical Engineers.

Bioattractors: dynamical systems theory and the evolution of regulatory processes

PubMed Central

Jaeger, Johannes; Monk, Nick

2014-01-01

In this paper, we illustrate how dynamical systems theory can provide a unifying conceptual framework for evolution of biological regulatory systems. Our argument is that the genotype–phenotype map can be characterized by the phase portrait of the underlying regulatory process. The features of this portrait – such as attractors with associated basins and their bifurcations – define the regulatory and evolutionary potential of a system. We show how the geometric analysis of phase space connects Waddington's epigenetic landscape to recent computational approaches for the study of robustness and evolvability in network evolution. We discuss how the geometry of phase space determines the probability of possible phenotypic transitions. Finally, we demonstrate how the active, self-organizing role of the environment in phenotypic evolution can be understood in terms of dynamical systems concepts. This approach yields mechanistic explanations that go beyond insights based on the simulation of evolving regulatory networks alone. Its predictions can now be tested by studying specific, experimentally tractable regulatory systems using the tools of modern systems biology. A systematic exploration of such systems will enable us to understand better the nature and origin of the phenotypic variability, which provides the substrate for evolution by natural selection. PMID:24882812

Quality Management in Astronomical Software and Data Systems

NASA Astrophysics Data System (ADS)

Radziwill, N. M.

2007-10-01

As the demand for more sophisticated facilities increases, the complexity of the technical and organizational challenges faced by operational space- and ground-based telescopes also increases. In many organizations, funding tends not to be proportional to this trend, and steps must be taken to cultivate a lean environment in both development and operations to consistently do more with less. To facilitate this transition, an organization must be aware of how it can meet quality-related goals, such as reducing variation, improving productivity of people and systems, streamlining processes, ensuring compliance with requirements (scientific, organizational, project, or regulatory), and increasing user satisfaction. Several organizations are already on this path. Quality-based techniques for the efficient, effective development of new telescope facilities and maintenance of existing facilities are described.

Regulatory environment and claims - limits and opportunities.

PubMed

Martin, Ambroise

2010-01-01

During the past decade, the use of claims became more and more important in many countries in relation to the increased awareness of consumer about the link between foods and health, offering to industry a valuable opportunity to differentiate and valorize their products and to promote innovation. However, more and more stringent regulations are developed, all based on the general principles adopted by the Codex Alimentarius Commission. In addition to the different regulatory processes and administrative requirements according to the country, the high level (and cost) of scientific substantiation of claims, the constraints introduced by nutrient profiles and the poor knowledge of the impact on consumer depending on the cultural contexts may limit these opportunities or, at least complicate their use. All these issues are briefly analyzed, highlighting some striking convergences and differences between countries. Copyright © 2010 S. Karger AG, Basel.

A Survey of Statistical Models for Reverse Engineering Gene Regulatory Networks

PubMed Central

Huang, Yufei; Tienda-Luna, Isabel M.; Wang, Yufeng

2009-01-01

Statistical models for reverse engineering gene regulatory networks are surveyed in this article. To provide readers with a system-level view of the modeling issues in this research, a graphical modeling framework is proposed. This framework serves as the scaffolding on which the review of different models can be systematically assembled. Based on the framework, we review many existing models for many aspects of gene regulation; the pros and cons of each model are discussed. In addition, network inference algorithms are also surveyed under the graphical modeling framework by the categories of point solutions and probabilistic solutions and the connections and differences among the algorithms are provided. This survey has the potential to elucidate the development and future of reverse engineering GRNs and bring statistical signal processing closer to the core of this research. PMID:20046885

Guidelines for Bacteriophage Product Certification.

PubMed

Fauconnier, Alan

2018-01-01

Following decades in the wilderness, bacteriophage therapy is now appearing as a credible antimicrobial strategy. However, this reemerging therapy does not rekindle without raising sensitive regulatory concerns. Indeed, whereas the European regulatory framework has been basically implemented to tackle ready-to-use pharmaceuticals produced on a large scale, bacteriophage therapy relies on a dynamic approach requiring a regulation on personalized medicine, nonexistent at present. Because of this, no guideline are currently available for addressing the scientific and regulatory issues specifically related to phage therapy medicinal products (PTMP).Pending to the implementation of an appropriate regulatory framework and to the development of ensuing guidelines, several avenues which might lead to PTMP regulatory compliance are explored here. Insights might come from the multi-strain dossier approach set up for particular animal vaccines, from the homologous group concept developed for the allergen products or from the licensing process for veterinary autogenous vaccines. Depending on national legislations, customized preparations prescribed as magistral formulas or to be used on a named-patient basis are possible regulatory approaches to be considered. However, these schemes are not optimal and should thus be regarded as transitional.

Regulatory acceptance and use of 3R models for pharmaceuticals and chemicals: expert opinions on the state of affairs and the way forward.

PubMed

Schiffelers, Marie-Jeanne W A; Blaauboer, Bas J; Bakker, Wieger E; Beken, Sonja; Hendriksen, Coenraad F M; Koëter, Herman B W M; Krul, Cyrille

2014-06-01

Pharmaceuticals and chemicals are subjected to regulatory safety testing accounting for approximately 25% of laboratory animal use in Europe. This testing meets various objections and has led to the development of a range of 3R models to Replace, Reduce or Refine the animal models. However, these models must overcome many barriers before being accepted for regulatory risk management purposes. This paper describes the barriers and drivers and options to optimize this acceptance process as identified by two expert panels, one on pharmaceuticals and one on chemicals. To untangle the complex acceptance process, the multilevel perspective on technology transitions is applied. This perspective defines influences at the micro-, meso- and macro level which need alignment to induce regulatory acceptance of a 3R model. This paper displays that there are many similar mechanisms within both sectors that prevent 3R models from becoming accepted for regulatory risk assessment and management. Shared barriers include the uncertainty about the value of the new 3R models (micro level), the lack of harmonization of regulatory requirements and acceptance criteria (meso level) and the high levels of risk aversion (macro level). In optimizing the process commitment, communication, cooperation and coordination are identified as critical drivers. Copyright © 2014 Elsevier Inc. All rights reserved.

Regulatory constraints as seen from the pharmaceutical industry.

PubMed

Galligani, G; David-Andersen, I; Fossum, B

2005-01-01

In Chile, Canada, Europe, Japan, and the USA, which are the main geographical areas for fish farming of high value fish such as salmonids, sea bass, sea bream, yellowtail and catfish, vaccination has been established as an important method for the prevention of infectious diseases. To make new vaccines available to the fish farming industry, pharmaceutical companies must comply with the regulatory framework for licensing of fish vaccines, which in recent years has become more regulated. Considerable scientific and regulatory skills are thus required to develop, document and license vaccines in accordance with the requirements in the different geographical areas. International co-operation to harmonise requirements for the licensing documentation is ongoing. Even though there are obvious benefits to the pharmaceutical industry from the harmonisation process, it may sometimes impose unreasonable requirements. The regulatory framework for fish vaccines clearly has an impact on the time for bringing a new fish vaccine to the market. Several hurdles need to be passed to complete the regulatory process, i.e. obtain a licence. Fulfilment of the rather detailed and extensive requirements for documentation of the production and controls, as well as safety and efficacy of the vaccine, represent a challenge to the pharmaceutical industry, as do the different national and regional licensing procedures. This paper describes regulatory constraints related to the documentation, the licensing process, the site of production and the continuing international harmonisation work, with emphasis on inactivated conventional fish vaccines.

Strengthening health professions regulation in Cambodia: a rapid assessment.

PubMed

Clarke, David; Duke, Jan; Wuliji, Tana; Smith, Alyson; Phuong, Keat; San, Un

2016-03-10

This paper describes a rapid assessment of Cambodia's current system for regulating its health professions. The assessment forms part of a co-design process to set strategic priorities for strengthening health profession regulation to improve the quality and safety of health services. A health system approach for strengthening health professions' regulation is underway and aims to support the Government of Cambodia's plans for scaling up its health workforce, improving health services' safety and quality, and meeting its Association of South East Asian Nations (ASEAN) obligations to facilitate trade in health care services. The assessment used a mixed methods approach including: A desktop review of key laws, plans, reports and other documents relating to the regulation of the health professions in Cambodia (medicine, dentistry, midwifery, nursing and pharmacy); Key informant interviews with stakeholders in Cambodia (The term "stakeholders" refers to government officials, people working on health professional regulation, people working for the various health worker training institutions and health workers at the national and provincial level); Surveys and questionnaires to assess Cambodian stakeholder knowledge of regulation; Self-assessments by members of the five Cambodian regulatory councils regarding key capacities and activities of high-performing regulatory bodies; and A rapid literature review to identify: The key functions of health professional regulation; The key issues affecting the Cambodian health sector (including relevant developments in the wider ASEAN region); and "Smart" health profession regulation practices of possible relevance to Cambodia. We found that the current regulatory system only partially meets Cambodia's needs. A number of key regulatory functions are being performed, but overall, the current system was not designed with Cambodia's specific needs in mind. The existing system is also overly complex, with considerable duplication and overlap between governance and regulatory arrangements for the five regulated professions. There is considerable scope for reform to the current regulatory system to better align the system to Cambodia's: Current needs and circumstances; Health system strategic priorities; and International obligations. Cambodia is also well placed to base its reformed regulatory system on recent developments of "smart regulatory practices" for health professionals.

Main regulatory pathways, key genes and microRNAs involved in flower formation and development of moso bamboo (Phyllostachys edulis).

PubMed

Ge, Wei; Zhang, Ying; Cheng, Zhanchao; Hou, Dan; Li, Xueping; Gao, Jian

2017-01-01

Moso bamboo is characterized by infrequent sexual reproduction and erratic flowering habit; however, the molecular biology of flower formation and development is not well studied in this species. We studied the molecular regulation mechanisms of moso bamboo development and flowering by selecting three key regulatory pathways: plant-pathogen interaction, plant hormone signal transduction and protein processing in endoplasmic reticulum at different stages of flowering in moso bamboo. We selected PheDof1, PheMADS14 and six microRNAs involved in the three pathways through KEGG pathway and cluster analysis. Subcellular localization, transcriptional activation, Western blotting, in situ hybridization and qRT-PCR were used to further investigate the expression patterns and regulatory roles of pivotal genes at different flower development stages. Differential expression patterns showed that PheDof1, PheMADS14 and six miRNAs may play vital regulatory roles in flower development and floral transition in moso bamboo. Our research paves way for further studies on metabolic regulatory networks and provides insight into the molecular regulation mechanisms of moso bamboo flowering and senescence. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

78 FR 310 - Draft Revision of Guidance for Industry on Providing Regulatory Submissions in Electronic Format...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-03

...ApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm253101.htm , http://www.regulations.../Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm253101.htm , http...), in a format that FDA can process, review, and archive. Currently, the Agency can process, review, and...

The writing approaches of secondary students.

PubMed

Lavelle, Ellen; Smith, Jennifer; O'Ryan, Leslie

2002-09-01

Research with college students has supported a model of writing approaches that defines the relationship between a writer and writing task along a deep and surface process continuum (Biggs, 1988). Based on that model, Lavelle (1993) developed the Inventory of Processes in College Composition which reflects students' motives and strategies as related to writing outcomes. It is also important to define the approaches of secondary students to better understand writing processes at that level, and development in written composition. This study was designed to define the writing approaches of secondary students by factor analysing students' responses to items regarding writing beliefs and writing strategies, and to compare the secondary approaches to those of college students. A related goal was to explore the relationships of the secondary writing approaches to perceived self-regulatory efficacy for writing (Zimmerman & Bandura, 1994), writing preferences, and writing outcomes. The initial, factor analytic phase involved 398 junior level high school students (11th grade) enrolled in a mandatory language arts class at each of three large Midwestern high schools (USA). Then, 49 junior level students enrolled in two language arts classes participated as subjects in the second phase. Classroom teachers administered the Inventory of Processes in College Composition (Lavelle, 1993), which contained 72 true-or-false items regarding writing beliefs and strategies, during regular class periods. Data were factor analysed and the structure compared to that of college students. In the second phase, the new inventory, Inventory of Processes in Secondary Composition, was administered in conjunction with the Perceived Self-Regulatory Efficacy for Writing Inventory (Zimmerman & Bandura, 1994), and a writing preferences survey. A writing sample and grade in Language Arts classes were obtained and served as outcome variables. The factor structure of secondary writing reflected three process dimensions. The first factor, Elaborative-Expressive, describes a writing strategy based on personal investment and audience concern. The second factor, Planful-Procedural, denotes sticking to a plan, following the rules, and 'preparing' for writing. Achieving-Competitive, the third factor, reflects a 'teacher pleasing' strategy or doing only what needs to be done to get a good grade. Two factors from the college model, Elaborative and Procedural, were replicated, and two were not, Reflective-Revision and Low Self-Efficacy. Regression analyses supported that the processes in writing under a timed condition are different from those used when writing over time, and that students' perceptions of writing self-regulatory efficacy were predictive of writing success under both conditions.

Proceedings: international regulatory considerations on development pathways for cell therapies.

PubMed

Feigal, Ellen G; Tsokas, Katherine; Viswanathan, Sowmya; Zhang, Jiwen; Priest, Catherine; Pearce, Jonathan; Mount, Natalie

2014-08-01

Regenerative medicine is a rapidly evolving field that faces novel scientific and regulatory challenges. In September 2013, the International Workshop on Regulatory Pathways for Cell Therapies was convened to discuss the nature of these challenges and potential solutions and to highlight opportunities for potential convergence between different regulatory bodies that might assist the field's development. The workshop discussions generated potentially actionable steps in five main areas that could mitigate cell therapy development pathway risk and accelerate moving promising therapies to patients. These included the need for convergence of regulatory guidelines on donor eligibility and suitability of lines for use in clinical trials and subsequent commercialization for cell therapies to move forward on a global basis; the need to challenge and encourage investigators in the regenerative medicine field to share information and provide examples of comparability studies related to master cell banks; the need for convergence of guidelines across regulatory jurisdictions on requirements for tumorigenicity studies, based on particular cell types and on biodistribution studies; the need to increase transparency in sharing clinical trial information more broadly and disseminating results more rapidly; and the need to establish a forum for sharing the experiences of various approaches being developed to expedite regulatory approvals and access for patients to innovative cell and regenerative therapies in the different regulatory jurisdictions and to assess their potential strengths and weaknesses. ©AlphaMed Press.

Update: the role of FoxP3 in allergic disease.

PubMed

Paik, Young; Dahl, Matthew; Fang, Deyu; Calhoun, Karen

2008-06-01

T-regulatory cells play a key role in allergic and asthmatic inflammatory airway diseases. This review discusses the importance of a critical gene associated with T-regulatory cells. Forkhead box P3 is a forkhead-winged helix transcription factor gene involved in immune function in allergy and asthma. Recently, many functions of forkhead box P3 and its influence on the immune system have been elucidated. T-regulatory cells that are CD4+CD25+ and express forkhead box P3, influence the development and expression of atopy and allergic response. The exact mechanisms are not yet delineated, but multiple recent studies provide greater understanding of the mechanism of forkhead box P3 and its influence on these T-regulatory cells. Greater understanding of the molecular and immunological mechanisms underlying the T-regulatory cells and forkhead box P3 will permit the development of targeted treatment modalities to influence disease processes such as allergic rhinitis and bronchial asthma.

Public Policy and Pharmaceutical Innovation

PubMed Central

Grabowski, Henry G.

1982-01-01

Historically, new drug introductions have played a central role in medical progress and the availability of cost-effective therapies. Nevertheless, public policy toward pharmaceuticals has been characterized in recent times by increasingly stringent regulatory controls, shorter effective patent terms, and increased encouragement of generic product usage. This has had an adverse effect on the incentives and capabilities of firms to undertake new drug research and development activity. The industry has experienced sharply rising research and development costs, declining annual new drug introductions, and fewer independent sources of drug development. This paper considers the effects of government regulatory policies on the pharmaceutical innovation process from several related perspectives. It also examines the merits of current public policy proposals designed to stimulate drug innovation including patent restoration and various regulatory reform measures. PMID:10309721

A Personal Perspective on the Initial Federal Health-Based Regulation to Remove Lead from Gasoline

PubMed Central

Bridbord, Kenneth; Hanson, David

2009-01-01

Objective This article describes the personal experience and perspective of the authors, who had primary responsibility for drafting the initial health-based regulation limiting lead content of gasoline during the early 1970s while employed by the U.S. Environmental Protection Agency (EPA). Data source Information used by the U.S. EPA in developing the initial health-based regulation limiting lead content of gasoline in December 1973 and studies documenting the impact of that and subsequent actions. Data extraction Among the lessons learned from this experience is the importance of having input from independent scientists to the regulatory decision-making process. This also demonstrates the critical role of independent peer-reviewed research, such as that supported by the National Institutes of Health, as well as research conducted by scientists from the Centers for Disease Control and Prevention, in delineating the consequences of lead exposure in the population. Data synthesis Removal of lead from gasoline in the United States has been described as one of the great public health achievements of the 20th century, but it almost did not happen. The experience of the authors in developing this regulation may be helpful to others involved in developing health-based regulatory policy in the future. Conclusion The initial U.S. EPA health-based regulation to remove lead from gasoline is clearly an example where science successfully affected public policy. The leadership of the U.S. EPA at that time deserves much credit for establishing an atmosphere in which this was possible. PMID:19672397

Ask the experts: the challenges and benefits of flow chemistry to optimize drug development.

PubMed

Anderson, Neal; Gernaey, Krist V; Jamison, Timothy F; Kircher, Manfred; Wiles, Charlotte; Leadbeater, Nicholas E; Sandford, Graham; Richardson, Paul

2012-09-01

Against a backdrop of a struggling economic and regulatory climate, pharmaceutical companies have recently been forced to develop new ways to provide more efficient technology to meet the demands of a competitive drug industry. This issue, coupled with an increase in patent legislation and a rising generics market, makes these themes common issues in the growth of drug development. As a consequence, the importance of process chemistry and scale-up has never been more under the spotlight. Future Medicinal Chemistry wishes to share the thoughts and opinions of a variety of experts from this field, discussing issues concerning the use of flow chemistry to optimize drug development, the potential regulatory and environmental challenges faced with this, and whether the academic and industrial sectors could benefit from a more harmonized system relevant to process chemistry.

Mesenchymal Stem Cells as Therapeutics Agents: Quality and Environmental Regulatory Aspects

PubMed Central

Sabata, Roger; Verges, Josep; Zugaza, José L.; Ruiz, Adolfina; Clares, Beatriz

2016-01-01

Mesenchymal stem cells (MSCs) are one of the main stem cells that have been used for advanced therapies and regenerative medicine. To carry out the translational clinical application of MSCs, their manufacturing and administration in human must be controlled; therefore they should be considered as medicine: stem cell-based medicinal products (SCMPs). The development of MSCs as SCMPs represents complicated therapeutics due to their extreme complex nature and rigorous regulatory oversights. The manufacturing process of MSCs needs to be addressed in clean environments in compliance with requirements of Good Manufacturing Practice (GMP). Facilities should maintain these GMP conditions according to international and national medicinal regulatory frameworks that introduce a number of specifications in order to produce MSCs as safe SCMPs. One of these important and complex requirements is the environmental monitoring. Although a number of environmental requirements are clearly defined, some others are provided as recommendations. In this review we aim to outline the current issues with regard to international guidelines which impact environmental monitoring in cleanrooms and clean areas for the manufacturing of MSCs. PMID:27999600

The Regulatory Evaluation of Vaccines for Human Use.

PubMed

Baylor, Norman W

2016-01-01

A vaccine is an immunogen, the administration of which is intended to stimulate the immune system to result in the prevention, amelioration, or therapy of any disease or infection (US Food and Drug Administration. Guidance for Industry: content and format of chemistry, manufacturing, and controls information and establishment description information for a vaccine or related product). A vaccine may be a live attenuated preparation of microorganisms, inactivated (killed) whole organisms, living irradiated cells, crude fractions, or purified immunogens, including those derived from recombinant DNA in a host cell, conjugates formed by covalent linkage of components, synthetic antigens, polynucleotides (such as the plasmid DNA vaccines), living vectored cells expressing specific heterologous immunogens, or cells pulsed with immunogen. Vaccines are highly complex products that differ from small molecule drugs because of the biological nature of the source materials such as those derived from microorganisms as well as the various cell substrates from which some are derived. Regardless of the technology used, because of their complexities, vaccines must undergo extensive characterization and testing. Special expertise and procedures are needed for their manufacture, control, and regulation. The Food and Drug Administration (FDA) is the National Regulatory Authority (NRA) in the United States responsible for assuring quality, safety, and effectiveness of all human medical products, including vaccines for human use.The Center for Biologics Evaluation and Research (CBER) within the US FDA is responsible for overseeing the regulation of therapeutic and preventative vaccines against infectious diseases. Authority for the regulation of vaccines resides in Section 351 of the Public Health Service Act and specific sections of the Federal Food, Drug, and Cosmetic Act (FD&C). Vaccines are regulated as biologics and licensed based on the demonstration of safety and effectiveness. The vaccine development process can be divided into two major categories: those events that are not under the regulatory authority of the FDA and are exploratory in nature and those events that are subject to regulatory authority by the FDA. Exploratory events or research and development cover basic research drug discovery processes that occur before the sponsor submits an investigational new drug application (IND) to the FDA. There are four main stages of vaccine development under the purview of regulatory authorities: preclinical, clinical (IND), licensing, and post-licensure. Throughout their life cycle from preclinical evaluation to post-licensure lot release testing, vaccines are subject to rigorous testing and oversight by manufacturers and NRAs. In this chapter an overview of the regulatory evaluation and testing requirements for vaccines is presented.

Analysis of environmental regulatory proposals: Its your chance to influence policy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Veil, J.A.

1994-03-02

As part of the regulatory development process, the US Envirorunental Protection Agency (EPA) collects data, makes various assumptions about the data, and analyzes the data. Although EPA acts in good faith, the agency cannot always be aware of all relevant data, make only appropriate assumptions, and use applicable analytical methods. Regulated industries must carefully must carefully review every component of the regulatory decision-making process to identify misunderstandings and errors and to supply additional data that is relevant to the regulatory action. This paper examines three examples of how EPA`s data, assumptions, and analytical methods have been critiqued. The first twomore » examples involve EPA`s cost-effectiveness (CE) analyses prepared for the offshore oil and gas effluent limitations guidelines and as part of EPA Region 6`s general permit for coastal waters of Texas and Louisiana. A CE analysis regulations to the incremental amount of pollutants that would be removed by the recommended treatment processes. The third example, although not involving a CE analysis, demonstrates how the use of non-representative data can influence the outcome of an analysis.« less

Sterile products: advances and challenges in formulation, manufacturing and regulatory aspects--a regulatory review perspective.

PubMed

Hussong, David

2010-09-01

For several decades, the FDA has undertaken many initiatives to improve the quality and safety of sterile drug products. In recent years, efforts have also been undertaken to accelerate the rate for application approval by adding earlier involvement of microbiology reviewers in drug development. Product and manufacturing process development, as well as safe use and product design, are among the elements of enhanced technical involvement. An overview of the product quality microbiology aspects for sterile drugs is provided.

CoryneRegNet: An ontology-based data warehouse of corynebacterial transcription factors and regulatory networks

PubMed Central

Baumbach, Jan; Brinkrolf, Karina; Czaja, Lisa F; Rahmann, Sven; Tauch, Andreas

2006-01-01

Background The application of DNA microarray technology in post-genomic analysis of bacterial genome sequences has allowed the generation of huge amounts of data related to regulatory networks. This data along with literature-derived knowledge on regulation of gene expression has opened the way for genome-wide reconstruction of transcriptional regulatory networks. These large-scale reconstructions can be converted into in silico models of bacterial cells that allow a systematic analysis of network behavior in response to changing environmental conditions. Description CoryneRegNet was designed to facilitate the genome-wide reconstruction of transcriptional regulatory networks of corynebacteria relevant in biotechnology and human medicine. During the import and integration process of data derived from experimental studies or literature knowledge CoryneRegNet generates links to genome annotations, to identified transcription factors and to the corresponding cis-regulatory elements. CoryneRegNet is based on a multi-layered, hierarchical and modular concept of transcriptional regulation and was implemented by using the relational database management system MySQL and an ontology-based data structure. Reconstructed regulatory networks can be visualized by using the yFiles JAVA graph library. As an application example of CoryneRegNet, we have reconstructed the global transcriptional regulation of a cellular module involved in SOS and stress response of corynebacteria. Conclusion CoryneRegNet is an ontology-based data warehouse that allows a pertinent data management of regulatory interactions along with the genome-scale reconstruction of transcriptional regulatory networks. These models can further be combined with metabolic networks to build integrated models of cellular function including both metabolism and its transcriptional regulation. PMID:16478536

Steps towards the international regulatory acceptance of non-animal methodology in safety assessment.

PubMed

Sewell, Fiona; Doe, John; Gellatly, Nichola; Ragan, Ian; Burden, Natalie

2017-10-01

The current animal-based paradigm for safety assessment must change. In September 2016, the UK National Centre for Replacement, Refinement and Reduction of Animals in Research (NC3Rs) brought together scientists from regulatory authorities, academia and industry to review progress in bringing new methodology into regulatory use, and to identify ways to expedite progress. Progress has been slow. Science is advancing to make this possible but changes are necessary. The new paradigm should allow new methodology to be adopted once it is developed rather than being based on a fixed set of studies. Regulatory authorities can help by developing Performance-Based Standards. The most pressing need is in repeat dose toxicology, although setting standards will be more complex than in areas such as sensitization. Performance standards should be aimed directly at human safety, not at reproducing the results of animal studies. Regulatory authorities can also aid progress towards the acceptance of non-animal based methodology by promoting "safe-haven" trials where traditional and new methodology data can be submitted in parallel to build up experience in the new methods. Industry can play its part in the acceptance of new methodology, by contributing to the setting of performance standards and by actively contributing to "safe-haven" trials. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Bayesian parameter inference for stochastic biochemical network models using particle Markov chain Monte Carlo

PubMed Central

Golightly, Andrew; Wilkinson, Darren J.

2011-01-01

Computational systems biology is concerned with the development of detailed mechanistic models of biological processes. Such models are often stochastic and analytically intractable, containing uncertain parameters that must be estimated from time course data. In this article, we consider the task of inferring the parameters of a stochastic kinetic model defined as a Markov (jump) process. Inference for the parameters of complex nonlinear multivariate stochastic process models is a challenging problem, but we find here that algorithms based on particle Markov chain Monte Carlo turn out to be a very effective computationally intensive approach to the problem. Approximations to the inferential model based on stochastic differential equations (SDEs) are considered, as well as improvements to the inference scheme that exploit the SDE structure. We apply the methodology to a Lotka–Volterra system and a prokaryotic auto-regulatory network. PMID:23226583

Developing Mindfulness in College Students through Movement-Based Courses: Effects on Self-Regulatory Self-Efficacy, Mood, Stress, and Sleep Quality

ERIC Educational Resources Information Center

Caldwell, Karen; Harrison, Mandy; Adams, Marianne; Quin, Rebecca H.; Greeson, Jeffrey

2010-01-01

Objective: This study examined whether mindfulness increased through participation in movement-based courses and whether changes in self-regulatory self-efficacy, mood, and perceived stress mediated the relationship between increased mindfulness and better sleep. Participants: 166 college students enrolled in the 2007-2008 academic year in 15 week…

High-risk medical devices, children and the FDA: regulatory challenges facing pediatric mechanical circulatory support devices.

PubMed

Almond, Christopher S D; Chen, Eric A; Berman, Michael R; Less, Joanne R; Baldwin, J Timothy; Linde-Feucht, Sarah R; Hoke, Tracey R; Pearson, Gail D; Jenkins, Kathy; Duncan, Brian W; Zuckerman, Bram D

2007-01-01

Pediatric mechanical circulatory support is a critical unmet need in the United States. Infant- and child-sized ventricular assist devices are currently being developed largely through federal contracts and grants through the National Heart, Lung, and Blood Institute (NHLBI). Human testing and marketing of high-risk devices for children raises epidemiologic and regulatory issues that will need to be addressed. Leaders from the US Food and Drug Administration (FDA), NHLBI, academic pediatric community, and industry convened in January 2006 for the first FDA Workshop on the Regulatory Process for Pediatric Mechanical Circulatory Support Devices. The purpose was to provide the pediatric community with an overview of the federal regulatory process for high-risk medical devices and to review the challenges specific to the development and regulation of pediatric mechanical circulatory support devices. Pediatric mechanical circulatory support present significant epidemiologic, logistic, and financial challenges to industry, federal regulators, and the pediatric community. Early interactions with the FDA, shared appreciation of challenges, and careful planning will be critical to avoid unnecessary delays in making potentially life-saving devices available for children. Collaborative efforts to address these challenges are warranted.

NRC safety research in support of regulation - FY 1994. Volume 9

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

This report, the tenth in a series of annual reports, was prepared in response to congressional inquiries concerning how nuclear regulatory research is used. It summarizes the accomplishments of the Office of Nuclear Regulatory Research during FY 1994. The goal of the Office of Nuclear Regulatory Research (RES) is to ensure the availability of sound technical bases for timely rulemaking and related decisions in support of NRC regulatory/licensing/inspection activities. RES also has responsibilities related to the resolution of generic safety issues and to the review of licensee submittals regarding individual plant examinations. It is the responsibility of RES to conductmore » the NRC`s rulemaking process, including the issuance of regulatory guides and rules that govern NRC licensed activities.« less

Regulating outdoor advertisement boards; employing spatial decision support system to control urban visual pollution

NASA Astrophysics Data System (ADS)

Wakil, K.; Hussnain, MQ; Tahir, A.; Naeem, M. A.

2016-06-01

Unmanaged placement, size, location, structure and contents of outdoor advertisement boards have resulted in severe urban visual pollution and deterioration of the socio-physical living environment in urban centres of Pakistan. As per the regulatory instruments, the approval decision for a new advertisement installation is supposed to be based on the locational density of existing boards and their proximity or remoteness to certain land- uses. In cities, where regulatory tools for the control of advertisement boards exist, responsible authorities are handicapped in effective implementation due to the absence of geospatial analysis capacity. This study presents the development of a spatial decision support system (SDSS) for regularization of advertisement boards in terms of their location and placement. The knowledge module of the proposed SDSS is based on provisions and restrictions prescribed in regulatory documents. While the user interface allows visualization and scenario evaluation to understand if the new board will affect existing linear density on a particular road and if it violates any buffer restrictions around a particular land use. Technically the structure of the proposed SDSS is a web-based solution which includes open geospatial tools such as OpenGeo Suite, GeoExt, PostgreSQL, and PHP. It uses three key data sets including road network, locations of existing billboards and building parcels with land use information to perform the analysis. Locational suitability has been calculated using pairwise comparison through analytical hierarchy process (AHP) and weighted linear combination (WLC). Our results indicate that open geospatial tools can be helpful in developing an SDSS which can assist solving space related iterative decision challenges on outdoor advertisements. Employing such a system will result in effective implementation of regulations resulting in visual harmony and aesthetic improvement in urban communities.

The Use of Regulatory Air Quality Models to Develop Successful Ozone Attainment Strategies

NASA Astrophysics Data System (ADS)

Canty, T. P.; Salawitch, R. J.; Dickerson, R. R.; Ring, A.; Goldberg, D. L.; He, H.; Anderson, D. C.; Vinciguerra, T.

2015-12-01

The Environmental Protection Agency (EPA) recently proposed lowering the 8-hr ozone standard to between 65-70 ppb. Not all regions of the U.S. are in attainment of the current 75 ppb standard and it is expected that many regions currently in attainment will not meet the future, lower surface ozone standard. Ozone production is a nonlinear function of emissions, biological processes, and weather. Federal and state agencies rely on regulatory air quality models such as the Community Multi-Scale Air Quality (CMAQ) model and Comprehensive Air Quality Model with Extensions (CAMx) to test ozone precursor emission reduction strategies that will bring states into compliance with the National Ambient Air Quality Standards (NAAQS). We will describe various model scenarios that simulate how future limits on emission of ozone precursors (i.e. NOx and VOCs) from sources such as power plants and vehicles will affect air quality. These scenarios are currently being developed by states required to submit a State Implementation Plan to the EPA. Projections from these future case scenarios suggest that strategies intended to control local ozone may also bring upwind states into attainment of the new NAAQS. Ground based, aircraft, and satellite observations are used to ensure that air quality models accurately represent photochemical processes within the troposphere. We will highlight some of the improvements made to the CMAQ and CAMx model framework based on our analysis of NASA observations obtained by the OMI instrument on the Aura satellite and by the DISCOVER-AQ field campaign.

Modeling in the quality by design environment: Regulatory requirements and recommendations for design space and control strategy appointment.

PubMed

Djuris, Jelena; Djuric, Zorica

2017-11-30

Mathematical models can be used as an integral part of the quality by design (QbD) concept throughout the product lifecycle for variety of purposes, including appointment of the design space and control strategy, continual improvement and risk assessment. Examples of different mathematical modeling techniques (mechanistic, empirical and hybrid) in the pharmaceutical development and process monitoring or control are provided in the presented review. In the QbD context, mathematical models are predominantly used to support design space and/or control strategies. Considering their impact to the final product quality, models can be divided into the following categories: high, medium and low impact models. Although there are regulatory guidelines on the topic of modeling applications, review of QbD-based submission containing modeling elements revealed concerns regarding the scale-dependency of design spaces and verification of models predictions at commercial scale of manufacturing, especially regarding real-time release (RTR) models. Authors provide critical overview on the good modeling practices and introduce concepts of multiple-unit, adaptive and dynamic design space, multivariate specifications and methods for process uncertainty analysis. RTR specification with mathematical model and different approaches to multivariate statistical process control supporting process analytical technologies are also presented. Copyright © 2017 Elsevier B.V. All rights reserved.

Canadian regulatory requirements for recombinant fish vaccines.

PubMed

Sethi, M S; Gifford, G A; Samagh, B S

1997-01-01

In Canada, veterinary biological products derived by using conventional and new techniques of biotechnology are licensed and regulated under the Health of Animals Act and Regulations. Biological products include vaccines, bacterins, bacterin-toxoids and diagnostic kits which are used for the prevention, treatment or diagnosis of infectious diseases in all species of animals, including fish. Veterinary biologicals are licensed on the basis of fulfillment of four criteria: purity, potency, safety and efficacy. A risk-based approach is used to evaluate the safety of the product in target species, as well as non-target species, humans and the environment. On the basis of biological characteristics, biotechnology derived veterinary biologicals have been divided into two broad categories, high and low risk products. The paper describes the regulatory framework for the licensing of veterinary biologicals in Canada, with emphasis on the regulatory considerations for recombinant fish vaccines. Stages of movement of the product from research in a contained laboratory facility to a fully licensed product for free sale are discussed. The requirements for field testing and environmental assessment involved in these stages are highlighted. Manufacturers and researchers who intend to commercialize experimental vaccines are encouraged to consult with the Veterinary Biologics and Biotechnology Section early in the product development process so that the research data and quality assurance documentation are consistent with regulatory requirements.

Biomarkers as drug development tools: discovery, validation, qualification and use.

PubMed

Kraus, Virginia B

2018-06-01

The 21st Century Cures Act, approved in the USA in December 2016, has encouraged the establishment of the national Precision Medicine Initiative and the augmentation of efforts to address disease prevention, diagnosis and treatment on the basis of a molecular understanding of disease. The Act adopts into law the formal process, developed by the FDA, of qualification of drug development tools, including biomarkers and clinical outcome assessments, to increase the efficiency of clinical trials and encourage an era of molecular medicine. The FDA and European Medicines Agency (EMA) have developed similar processes for the qualification of biomarkers intended for use as companion diagnostics or for development and regulatory approval of a drug or therapeutic. Biomarkers that are used exclusively for the diagnosis, monitoring or stratification of patients in clinical trials are not subject to regulatory approval, although their qualification can facilitate the conduct of a trial. In this Review, the salient features of biomarker discovery, analytical validation, clinical qualification and utilization are described in order to provide an understanding of the process of biomarker development and, through this understanding, convey an appreciation of their potential advantages and limitations.

A model of gene expression based on random dynamical systems reveals modularity properties of gene regulatory networks.

PubMed

Antoneli, Fernando; Ferreira, Renata C; Briones, Marcelo R S

2016-06-01

Here we propose a new approach to modeling gene expression based on the theory of random dynamical systems (RDS) that provides a general coupling prescription between the nodes of any given regulatory network given the dynamics of each node is modeled by a RDS. The main virtues of this approach are the following: (i) it provides a natural way to obtain arbitrarily large networks by coupling together simple basic pieces, thus revealing the modularity of regulatory networks; (ii) the assumptions about the stochastic processes used in the modeling are fairly general, in the sense that the only requirement is stationarity; (iii) there is a well developed mathematical theory, which is a blend of smooth dynamical systems theory, ergodic theory and stochastic analysis that allows one to extract relevant dynamical and statistical information without solving the system; (iv) one may obtain the classical rate equations form the corresponding stochastic version by averaging the dynamic random variables (small noise limit). It is important to emphasize that unlike the deterministic case, where coupling two equations is a trivial matter, coupling two RDS is non-trivial, specially in our case, where the coupling is performed between a state variable of one gene and the switching stochastic process of another gene and, hence, it is not a priori true that the resulting coupled system will satisfy the definition of a random dynamical system. We shall provide the necessary arguments that ensure that our coupling prescription does indeed furnish a coupled regulatory network of random dynamical systems. Finally, the fact that classical rate equations are the small noise limit of our stochastic model ensures that any validation or prediction made on the basis of the classical theory is also a validation or prediction of our model. We illustrate our framework with some simple examples of single-gene system and network motifs. Copyright © 2016 Elsevier Inc. All rights reserved.

Identification of key regulators in glycogen utilization in E. coli based on the simulations from a hybrid functional Petri net model.

PubMed

Tian, Zhongyuan; Fauré, Adrien; Mori, Hirotada; Matsuno, Hiroshi

2013-01-01

Glycogen and glucose are two sugar sources available during the lag phase of E. coli, but the mechanism that regulates their utilization is still unclear. Attempting to unveil the relationship between glucose and glycogen, we propose an integrated hybrid functional Petri net (HFPN) model including glycolysis, PTS, glycogen metabolic pathway, and their internal regulatory systems. By comparing known biological results to this model, basic necessary regulatory mechanism for utilizing glucose and glycogen were identified as a feedback circuit in which HPr and EIIAGlc play key roles. Based on this regulatory HFPN model, we discuss the process of glycogen utilization in E. coli in the context of a systematic understanding of carbohydrate metabolism.

Genes uniquely expressed in human growth plate chondrocytes uncover a distinct regulatory network.

PubMed

Li, Bing; Balasubramanian, Karthika; Krakow, Deborah; Cohn, Daniel H

2017-12-20

Chondrogenesis is the earliest stage of skeletal development and is a highly dynamic process, integrating the activities and functions of transcription factors, cell signaling molecules and extracellular matrix proteins. The molecular mechanisms underlying chondrogenesis have been extensively studied and multiple key regulators of this process have been identified. However, a genome-wide overview of the gene regulatory network in chondrogenesis has not been achieved. In this study, employing RNA sequencing, we identified 332 protein coding genes and 34 long non-coding RNA (lncRNA) genes that are highly selectively expressed in human fetal growth plate chondrocytes. Among the protein coding genes, 32 genes were associated with 62 distinct human skeletal disorders and 153 genes were associated with skeletal defects in knockout mice, confirming their essential roles in skeletal formation. These gene products formed a comprehensive physical interaction network and participated in multiple cellular processes regulating skeletal development. The data also revealed 34 transcription factors and 11,334 distal enhancers that were uniquely active in chondrocytes, functioning as transcriptional regulators for the cartilage-selective genes. Our findings revealed a complex gene regulatory network controlling skeletal development whereby transcription factors, enhancers and lncRNAs participate in chondrogenesis by transcriptional regulation of key genes. Additionally, the cartilage-selective genes represent candidate genes for unsolved human skeletal disorders.

U.S. regulatory research program for implementation of burnup credit in transport casks

DOT National Transportation Integrated Search

2001-09-10

In 1999 the U.S. Nuclear Regulatory Commission (U.S. NRC) initiated a research program to : support the development of technical bases and guidance that would facilitate the implementation of : burnup credit into licensing activities for transport an...

Human Genome Editing in the Clinic: New Challenges in Regulatory Benefit-Risk Assessment.

PubMed

Abou-El-Enein, Mohamed; Cathomen, Toni; Ivics, Zoltán; June, Carl H; Renner, Matthias; Schneider, Christian K; Bauer, Gerhard

2017-10-05

As genome editing rapidly progresses toward the realization of its clinical promise, assessing the suitability of current tools and processes used for its benefit-risk assessment is critical. Although current regulations may initially provide an adequate regulatory framework, improvements are recommended to overcome several existing technology-based safety and efficacy issues. Copyright © 2017 Elsevier Inc. All rights reserved.

Cross-Cutting issues in Regulatory Supervision of Spent Fuel Radioactive Waste and Radioactively Contaminated Land in North-West Russia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sneve, M. K.; Smith, G. M.

2006-07-01

The Norwegian Government is promoting improvements in radiation protection and nuclear safety in North-West Russia. Among priority areas there is the improvement of spent nuclear fuel and radioactive waste management, as well as remediation operations at the Shore Technical Bases operated by Federal Enterprise SevRAO at Andreeva Bay and Gremikha on the Kola Peninsula. The extreme radiological conditions at these sites present novel difficulties for regulatory supervision of operations. The situation at these sites is such that the existing regulations are applicable, and actions to remedy the situation are not permitted under the current regulatory regime. An improved regulatory process,more » including development of special norms and rules, is required to take account of this unusual situation. The Norwegian strategy includes not only support to industrial projects, but also support to Russian Federation regulatory bodies, to ensure that work is carried out in compliance with Russian Federation law, taking account of international recommendations and other national good practice as relevant in the RF. Accordingly, the Norwegian Radiation Protection Authority has set up a programme of cooperation with the Federal Medical-Biological Agency (FMBA), which is the primary radiation protection authority in the RF. The work is carried out with technical input from the Russian Institute of Biophysics and with inputs from western technical support organisations. The overall objective of the work is to promote effective and efficient regulatory supervision of SevRAO activities at Andreeva Bay and Gremikha within the scope of responsibilities of FMBA. This paper describes the results of an initial threat assessment which allows consideration of the cross-cutting issues associated with developing an overall effective site management plan which deals with short- and long-term issues, and protection of workers as well as of the public and the environment, while achieving a timely and effective use of resources in order to solve the problems. (authors)« less

Gene regulation is governed by a core network in hepatocellular carcinoma.

PubMed

Gu, Zuguang; Zhang, Chenyu; Wang, Jin

2012-05-01

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and the mechanisms that lead to the disease are still relatively unclear. However, with the development of high-throughput technologies it is possible to gain a systematic view of biological systems to enhance the understanding of the roles of genes associated with HCC. Thus, analysis of the mechanism of molecule interactions in the context of gene regulatory networks can reveal specific sub-networks that lead to the development of HCC. In this study, we aimed to identify the most important gene regulations that are dysfunctional in HCC generation. Our method for constructing gene regulatory network is based on predicted target interactions, experimentally-supported interactions, and co-expression model. Regulators in the network included both transcription factors and microRNAs to provide a complete view of gene regulation. Analysis of gene regulatory network revealed that gene regulation in HCC is highly modular, in which different sets of regulators take charge of specific biological processes. We found that microRNAs mainly control biological functions related to mitochondria and oxidative reduction, while transcription factors control immune responses, extracellular activity and the cell cycle. On the higher level of gene regulation, there exists a core network that organizes regulations between different modules and maintains the robustness of the whole network. There is direct experimental evidence for most of the regulators in the core gene regulatory network relating to HCC. We infer it is the central controller of gene regulation. Finally, we explored the influence of the core gene regulatory network on biological pathways. Our analysis provides insights into the mechanism of transcriptional and post-transcriptional control in HCC. In particular, we highlight the importance of the core gene regulatory network; we propose that it is highly related to HCC and we believe further experimental validation is worthwhile.

Leading trends in environmental regulation that affect energy development. Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Steele, R V; Attaway, L D; Christerson, J A

1980-01-01

Major environmental issues that are likely to affect the implementation of energy technologies between now and the year 2000 are identified and assessed. The energy technologies specifically addressed are: oil recovery and processing; gas recovery and processing; coal liquefaction; coal gasification (surface); in situ coal gasification; direct coal combustion; advanced power systems; magnetohydrodynamics; surface oil shale retorting; true and modified in situ oil shale retorting; geothermal energy; biomass energy conversion; and nuclear power (fission). Environmental analyses of these technologies included, in addition to the main processing steps, the complete fuel cycle from resource extraction to end use. A comprehensive surveymore » of the environmental community (including environmental groups, researchers, and regulatory agencies) was carried out in parallel with an analysis of the technologies to identify important future environmental issues. Each of the final 20 issues selected by the project staff has the following common attributes: consensus of the environmental community that the issue is important; it is a likely candidate for future regulatory action; it deals with a major environmental aspect of energy development. The analyses of the 20 major issues address their environmental problem areas, current regulatory status, and the impact of future regulations. These analyses are followed by a quantitative assessment of the impact on energy costs and nationwide pollutant emissions of possible future regulations. This is accomplished by employing the Strategic Environmental Assessment System (SEAS) for a subset of the 20 major issues. The report concludes with a more general discussion of the impact of environmental regulatory action on energy development.« less

A Quantitative Acetylomic Analysis of Early Seed Development in Rice (Oryza sativa L.).

PubMed

Wang, Yifeng; Hou, Yuxuan; Qiu, Jiehua; Li, Zhiyong; Zhao, Juan; Tong, Xiaohong; Zhang, Jian

2017-06-27

PKA (protein lysine acetylation) is a critical post-translational modification that regulates various developmental processes, including seed development. However, the acetylation events and dynamics on a proteomic scale in this process remain largely unknown, especially in rice early seed development. We report the first quantitative acetylproteomic study focused on rice early seed development by employing a mass spectral-based (MS-based), label-free approach. A total of 1817 acetylsites on 1688 acetylpeptides from 972 acetylproteins were identified in pistils and seeds at three and seven days after pollination, including 268 acetyproteins differentially acetylated among the three stages. Motif-X analysis revealed that six significantly enriched motifs, such as (DxkK), (kH) and (kY) around the acetylsites of the identified rice seed acetylproteins. Differentially acetylated proteins among the three stages, including adenosine diphosphate (ADP) -glucose pyrophosphorylases (AGPs), PDIL1-1 (protein disulfide isomerase like 1-1), hexokinases, pyruvate dehydrogenase complex (PDC) and numerous other regulators that are extensively involved in the starch and sucrose metabolism, glycolysis/gluconeogenesis, tricarboxylic acid (TCA) cycle and photosynthesis pathways during early seed development. This study greatly expanded the rice acetylome dataset, and shed novel insight into the regulatory roles of PKA in rice early seed development.

Extension of quality-by-design concept to the early development phase of pharmaceutical R&D processes.

PubMed

Csóka, Ildikó; Pallagi, Edina; Paál, Tamás L

2018-03-27

Here, we propose the extension of the quality-by-design (QbD) concept to also fit the early development phases of pharmaceuticals by adding elements that are currently widely applied, but not yet included in the QbD model in a structured way. These are the introduction of a 'zero' preformulation phase (i.e., selection of drug substance, possible dosage forms and administration routes based on the evaluated therapeutic need); building in stakeholders' (industry, patient, and regulatory) requirements into the quality target product profile (QTTP); and the use of modern quality management tools during the composition and process design phase [collecting critical quality attributes (CQAs) and selection of CPPs) for (still laboratory-scale) design space (DS) development. Moreover, during industrial scale-up, CQAs (as well as critical process parameters; CPPs) can be changed; however, we recommend that the existing QbD elements are reconsidered and updated after this phase. Copyright © 2018 Elsevier Ltd. All rights reserved.

Preliminary identification of potentially disruptive scenarios at the Greater Confinement Disposal Facility, Area 5 of the Nevada Test Site

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guzowski, R.V.; Newman, G.

1993-12-01

The Greater Confinement Disposal location is being evaluated to determine whether defense-generated transuranic waste buried at this location complies with the Containment Requirements established by the US Environmental Protection Agency. One step in determining compliance is to identify those combinations of events and processes (scenarios) that define possible future states of the disposal system for which performance assessments must be performed. An established scenario-development procedure was used to identify a comprehensive set of mutually exclusive scenarios. To assure completeness, 761 features, events, processes, and other listings (FEPS) were compiled from 11 references. This number was reduced to 205 primarily throughmore » the elimination of duplications. The 205 FEPs were screened based on site-specific, goal-specific, and regulatory criteria. Four events survived screening and were used in preliminary scenario development: (1) exploratory drilling penetrates a GCD borehole, (2) drilling of a withdrawal/injection well penetrates a GCD borehole, (3) subsidence occurs at the RWMS, and (4) irrigation occurs at the RWMS. A logic diagram was used to develop 16 scenarios from the four events. No screening of these scenarios was attempted at this time. Additional screening of the currently retained events and processes will be based on additional data and information from site-characterization activities. When screening of the events and processes is completed, a final set of scenarios will be developed and screened based on consequence and probability of occurrence.« less

Assessing cumulative impacts to elk and mule deer in the Salmon River Basin, Idaho

DOE Office of Scientific and Technical Information (OSTI.GOV)

O'Neil, T.A.; Witmer, G.W.

1988-01-01

In this paper, we illustrate the method, using the potential for cumulative impacts to elk and mule deer from multiple hydroelectric development in the Salmon River Basin of Idaho. We attempted to incorporate knowledge of elk and mule deer habitat needs into a paradigm to assess cumulative impacts and aid in the regulatory decision making process. Undoubtedly, other methods could be developed based on different needs or constraints, but we offer this technique as a means to further refine cumulative impact assessment. Our approach is divided into three phases: analysis, evaluation, and documentation. 36 refs., 2 figs., 3 tabs.

Implementation of the fugitive emissions system program: The OxyChem experience

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deshmukh, A.

An overview is provided for the Fugitive Emissions System (FES) that has been implemented at Occidental Chemical in conjunction with the computer-based maintenance system called PassPort{reg_sign} developed by Indus Corporation. The goal of PassPort{reg_sign} FES program has been to interface with facilities data, equipment information, work standards and work orders. Along the way, several implementation hurdles had to be overcome before a monitoring and regulatory system could be standardized for the appropriate maintenance, process and environmental groups. This presentation includes step-by-step account of several case studies that developed during the implementation of the FES system.

Contamination in food from packaging material.

PubMed

Lau, O W; Wong, S K

2000-06-16

Packaging has become an indispensible element in the food manufacturing process, and different types of additives, such as antioxidants, stabilizers, lubricants, anti-static and anti-blocking agents, have also been developed to improve the performance of polymeric packaging materials. Recently the packaging has been found to represent a source of contamination itself through the migration of substances from the packaging into food. Various analytical methods have been developed to analyze the migrants in the foodstuff, and migration evaluation procedures based on theoretical prediction of migration from plastic food contact material were also introduced recently. In this paper, the regulatory control, analytical methodology, factors affecting the migration and migration evaluation are reviewed.

Regulation of Ocean Iron Fertilization (OIF): a Model for Balancing Research, Environmental and Policy Concerns

NASA Astrophysics Data System (ADS)

Leinen, M.; Lamotte, R.

2008-12-01

The potential of enhancing carbon sequestration by the biosphere for climate mitigation often raises questions of offsetting effects. These questions become more important as the scale of the enhancement increases. Ocean iron fertilization is accompanied by additional questions related to use of the ocean commons. The London Convention (LC) and London Protocol (LP), international treaties adopted in 1972 and 1996 respectively, were designed to prevent use of the ocean for disposal of toxic, harmful and radioactive pollutants. Recently the LC/LP has been called upon to decide whether climate mitigation activities, such as subseafloor injection of CO2 and OIF, are legal under the framework and, if so, how they should be regulated. The broad consultation with the science community by the LC/LP in developing their perspective, and the involvement of the NGO community in these deliberations, provides a model for the process that the international policy community can use to develop science-based regulatory guidelines for carbon mitigation projects involving the commons. And the substance of that emerging regulatory framework -- built on a national-level permitting process informed by internationally agreed guidelines and standards -- may also serve as a model for the oversight of other emerging technologies that take place in the global commons.

On the nature and consequences of early loss.

PubMed

Hofer, M A

1996-01-01

To describe how an animal model system can be used to explore basic questions about the nature of loss and the effects of early loss on later vulnerability to disease. The physiological and behavioral responses of infant rats to separation from their mothers are first described and then analyzed experimentally into component mechanisms. These studies have revealed an extensive layer of processes underlying the psychological constructs generally used to understand the response to loss. Hidden within the observable interactions of parent and offspring, we found a number of discrete sensorimotor, thermal, and nutrient-based events that have unexpected long-term regulatory effects on specific components of infant physiology and behavior. Release from all of these inhibitory and excitatory regulators together during maternal separation constitutes a novel mechanism by which the experience of loss can be translated into a complex patterned response. Evidence for early regulatory processes has also been found in monkey and human mother-infant interactions. Here they may well constitute the building blocks from which attachment and object representations develop. We and others have found long-term effects of loss, and of selective replacement of regulators, on behavioral development and on later vulnerability to disease. The results give us a new understanding of early attachment as a developmental force and of human grief as a risk to health.

Environmental Effects of Offshore Wind Development. Fiscal Year 2012 Progress Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Copping, Andrea E.; Hanna, Luke A.; Butner, R. Scott

Potential environmental effects of offshore wind (OSW) energy projects are not well understood, and regulatory agencies are required to make decisions in spite of substantial uncertainty about environmental impacts and their long-term consequences. An understanding of risks associated with interactions between OSW installations and aquatic receptors, including animals, habitats, and ecosystems, can help define key uncertainties and focus regulatory actions and scientific studies on interactions of most concern. To examine the environmental risks associated with OSW developments in the U.S. Pacific Northwest National Laboratory (PNNL) focused on the following four priority research areas in FY 2012: • Environmental Risk Evaluationmore » System (ERES) - Followed project developments on the two OSW projects that PNNL screened in FY 2011 for environmental consequence: Fishermen’s Energy off the coast of Atlantic City, NJ and LEEDCo. near Cleveland, OH in Lake Erie. • Tethys - Developed a smart knowledge base which houses environmental research, data and information pertaining to OSW energy: • Technical Assessment - Produced a new software to create an automated process of identifying and differentiating between flying organism such as birds and bats by using thermal imagery; and • North Atlantic Right Whales - Developed an environmental risk management system to mitigate the impacts on North Atlantic Right Whales (NARW) during installation and piledriving stages of OSW developments. By identifying and addressing the highest priority environmental risks for OSW devices and associated installations the ERES process assists project proponents, regulators, and stakeholders to engage in the most efficient and effective siting and permitting pathways.« less

A versatile petri net based architecture for modeling and simulation of complex biological processes.

PubMed

Nagasaki, Masao; Doi, Atsushi; Matsuno, Hiroshi; Miyano, Satoru

2004-01-01

The research on modeling and simulation of complex biological systems is getting more important in Systems Biology. In this respect, we have developed Hybrid Function Petri net (HFPN) that was newly developed from existing Petri net because of their intuitive graphical representation and their capabilities for mathematical analyses. However, in the process of modeling metabolic, gene regulatory or signal transduction pathways with the architecture, we have realized three extensions of HFPN, (i) an entity should be extended to contain more than one value, (ii) an entity should be extended to handle other primitive types, e.g. boolean, string, (iii) an entity should be extended to handle more advanced type called object that consists of variables and methods, are necessary for modeling biological systems with Petri net based architecture. To deal with it, we define a new enhanced Petri net called hybrid functional Petri net with extension (HFPNe). To demonstrate the effectiveness of the enhancements, we model and simulate with HFPNe four biological processes that are diffcult to represent with the previous architecture HFPN.

[Human resources for health in Ecuador's new model of care].

PubMed

Espinosa, Verónica; de la Torre, Daniel; Acuña, Cecilia; Cadena, Cristina

2017-06-08

Describe strategies implemented by Ecuador's Ministry of Public Health (MPH) to strengthen human resources for health leadership and respond to the new model of care, as a part of the reform process in the period 2012-2015. A documentary review was carried out of primary and secondary sources on development of human resources for health before and after the reform. In the study period, Ecuador developed a new institutional and regulatory framework for developing human resources for health to respond to the requirements of a model of care based on primary health care. The MPH consolidated its steering role by forging strategic partnerships, implementing human resources planning methods, and making an unprecedented investment in health worker training, hiring, and wage increases. These elements constitute the initial core for development of human resources for health policy and a health-services study program consistent with the reform's objectives. Within the framework of the reform carried out from 2012 to 2015, intersectoral work by the MPH has led to considerable achievements in development of human resources for health. Notable achievements include strengthening of the steering role, development and implementation of standards and regulatory instruments, creation of new professional profiles, and hiring of professionals to implement the comprehensive health care model, which helped to solve problems carried over from the years prior to the reform.

Uniform, optimal signal processing of mapped deep-sequencing data.

PubMed

Kumar, Vibhor; Muratani, Masafumi; Rayan, Nirmala Arul; Kraus, Petra; Lufkin, Thomas; Ng, Huck Hui; Prabhakar, Shyam

2013-07-01

Despite their apparent diversity, many problems in the analysis of high-throughput sequencing data are merely special cases of two general problems, signal detection and signal estimation. Here we adapt formally optimal solutions from signal processing theory to analyze signals of DNA sequence reads mapped to a genome. We describe DFilter, a detection algorithm that identifies regulatory features in ChIP-seq, DNase-seq and FAIRE-seq data more accurately than assay-specific algorithms. We also describe EFilter, an estimation algorithm that accurately predicts mRNA levels from as few as 1-2 histone profiles (R ∼0.9). Notably, the presence of regulatory motifs in promoters correlates more with histone modifications than with mRNA levels, suggesting that histone profiles are more predictive of cis-regulatory mechanisms. We show by applying DFilter and EFilter to embryonic forebrain ChIP-seq data that regulatory protein identification and functional annotation are feasible despite tissue heterogeneity. The mathematical formalism underlying our tools facilitates integrative analysis of data from virtually any sequencing-based functional profile.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haney, Thomas Jay

This report documents the Data Quality Objectives (DQOs) developed for the Idaho National Laboratory (INL) Site ambient air surveillance program. The development of the DQOs was based on the seven-step process recommended “for systematic planning to generate performance and acceptance criteria for collecting environmental data” (EPA 2006). The process helped to determine the type, quantity, and quality of data needed to meet current regulatory requirements and to follow U.S. Department of Energy guidance for environmental surveillance air monitoring design. It also considered the current air monitoring program that has existed at INL Site since the 1950s. The development of themore » DQOs involved the application of the atmospheric dispersion model CALPUFF to identify likely contamination dispersion patterns at and around the INL Site using site-specific meteorological data. Model simulations were used to quantitatively assess the probable frequency of detection of airborne radionuclides released by INL Site facilities using existing and proposed air monitors.« less

77 FR 72997 - Low-Level Waste Disposal

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-07

...-2011-0012] RIN 3150-AI92 Low-Level Waste Disposal AGENCY: Nuclear Regulatory Commission. ACTION... Regulatory Commission (NRC) is proposing to amend its regulations that govern low-level radioactive waste... development of criteria for waste acceptance based on the results of these analyses. These amendments will...

76 FR 66344 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-26

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving Proposed Rule Change... 31, 2011, Financial Industry Regulatory Authority, Inc. (``FINRA'') (f/k/a National Association of... consolidation process, see Information Notice, March 12, 2008 (Rulebook Consolidation Process). For convenience...

Establishing Policy Foundations and Regulatory Systems to Enhance Nursing Practice in the United Arab Emirates.

PubMed

Brownie, Sharon M; Hunter, Lyndal H; Aqtash, Salah; Day, Gary E

2015-01-01

In 2009, the United Arab Emirates (UAE) established a Nursing and Midwifery Council with a mandate to develop standards for the registration and regulation of nursing and midwifery and to strengthen the nursing and midwifery workforce. Priorities included workforce Emiratization and the development of regulatory standards to support advanced and speciality nursing practice and new models of care-particularly for the management of noncommunicable diseases. This article provides background, context for, and best practice inputs to the effort to provide one unified framework of nursing regulation and licensure across the whole of the UAE. This article is intended for nurse leaders, policy makers, and regulators who are reviewing or developing nursing regulatory processes and advancing nursing workforce capacity building activities; and nurse educators and nurses wishing to work in the UAE. © The Author(s) 2015.

Establishing Policy Foundations and Regulatory Systems to Enhance Nursing Practice in the United Arab Emirates

PubMed Central

Hunter, Lyndal H.; Aqtash, Salah; Day, Gary E.

2015-01-01

In 2009, the United Arab Emirates (UAE) established a Nursing and Midwifery Council with a mandate to develop standards for the registration and regulation of nursing and midwifery and to strengthen the nursing and midwifery workforce. Priorities included workforce Emiratization and the development of regulatory standards to support advanced and speciality nursing practice and new models of care—particularly for the management of noncommunicable diseases. This article provides background, context for, and best practice inputs to the effort to provide one unified framework of nursing regulation and licensure across the whole of the UAE. This article is intended for nurse leaders, policy makers, and regulators who are reviewing or developing nursing regulatory processes and advancing nursing workforce capacity building activities; and nurse educators and nurses wishing to work in the UAE. PMID:25944674

78 FR 50410 - Black Bear Development Holdings, LLC; Supplemental Notice that Initial Market-Based Rate Filing...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-19

... Black Bear Development Holdings, LLC's application for market-based rate authority, with an accompanying... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. ER13-2143-000] Black Bear Development Holdings, LLC; Supplemental Notice that Initial Market-Based Rate Filing Includes Request for...

Reconstructing directed gene regulatory network by only gene expression data.

PubMed

Zhang, Lu; Feng, Xi Kang; Ng, Yen Kaow; Li, Shuai Cheng

2016-08-18

Accurately identifying gene regulatory network is an important task in understanding in vivo biological activities. The inference of such networks is often accomplished through the use of gene expression data. Many methods have been developed to evaluate gene expression dependencies between transcription factor and its target genes, and some methods also eliminate transitive interactions. The regulatory (or edge) direction is undetermined if the target gene is also a transcription factor. Some methods predict the regulatory directions in the gene regulatory networks by locating the eQTL single nucleotide polymorphism, or by observing the gene expression changes when knocking out/down the candidate transcript factors; regrettably, these additional data are usually unavailable, especially for the samples deriving from human tissues. In this study, we propose the Context Based Dependency Network (CBDN), a method that is able to infer gene regulatory networks with the regulatory directions from gene expression data only. To determine the regulatory direction, CBDN computes the influence of source to target by evaluating the magnitude changes of expression dependencies between the target gene and the others with conditioning on the source gene. CBDN extends the data processing inequality by involving the dependency direction to distinguish between direct and transitive relationship between genes. We also define two types of important regulators which can influence a majority of the genes in the network directly or indirectly. CBDN can detect both of these two types of important regulators by averaging the influence functions of candidate regulator to the other genes. In our experiments with simulated and real data, even with the regulatory direction taken into account, CBDN outperforms the state-of-the-art approaches for inferring gene regulatory network. CBDN identifies the important regulators in the predicted network: 1. TYROBP influences a batch of genes that are related to Alzheimer's disease; 2. ZNF329 and RB1 significantly regulate those 'mesenchymal' gene expression signature genes for brain tumors. By merely leveraging gene expression data, CBDN can efficiently infer the existence of gene-gene interactions as well as their regulatory directions. The constructed networks are helpful in the identification of important regulators for complex diseases.

Enterprise Professional Development--Evaluating Learning

ERIC Educational Resources Information Center

Murphy, Gerald A.; Calway, Bruce A.

2010-01-01

Whilst professional development (PD) is an activity required by many regulatory authorities, the value that enterprises obtain from PD is often unknown, particularly when it involves development of knowledge. This paper discusses measurement techniques and processes and provides a review of established evaluation techniques, highlighting…

Animal models of neoplastic development.

PubMed

Pitot, H C

2001-01-01

The basic animal model for neoplastic development used by regulatory agencies is the two-year chronic bioassay developed more than 30 years ago and based on the presumed mechanism of action of a few potential chemical carcinogens. Since that time, a variety of other model carcinogenic systems have been developed, usually involving shorter duration, single organ endpoints, multistage models, and those in genetically-engineered mice. The chronic bioassay is still the "gold standard" of regulatory agencies despite a number of deficiencies, while in this country the use of shorter term assays based on single organ endpoints has not been popular. The multistage model of carcinogenesis in mouse epidermis actually preceded the development of the chronic two-year bioassay, but it was not until multistage models in other organ systems were developed that the usefulness of such systems became apparent. Recently, several genetically-engineered mouse lines involving mutations in proto-oncogenes and tumour suppressor genes have been proposed as additional model systems for use in regulatory decisions. It is likely that a combination of several of these model systems may be most useful in both practical and basic applications of cancer prevention and therapy.

Pathway-Based Analysis of Genome-Wide siRNA Screens Reveals the Regulatory Landscape of App Processing

PubMed Central

Camargo, Luiz Miguel; Zhang, Xiaohua Douglas; Loerch, Patrick; Caceres, Ramon Miguel; Marine, Shane D.; Uva, Paolo; Ferrer, Marc; de Rinaldis, Emanuele; Stone, David J.; Majercak, John; Ray, William J.; Yi-An, Chen; Shearman, Mark S.; Mizuguchi, Kenji

2015-01-01

The progressive aggregation of Amyloid-β (Aβ) in the brain is a major trait of Alzheimer's Disease (AD). Aβ is produced as a result of proteolytic processing of the β-amyloid precursor protein (APP). Processing of APP is mediated by multiple enzymes, resulting in the production of distinct peptide products: the non-amyloidogenic peptide sAPPα and the amyloidogenic peptides sAPPβ, Aβ40, and Aβ42. Using a pathway-based approach, we analyzed a large-scale siRNA screen that measured the production of different APP proteolytic products. Our analysis identified many of the biological processes/pathways that are known to regulate APP processing and have been implicated in AD pathogenesis, as well as revealing novel regulatory mechanisms. Furthermore, we also demonstrate that some of these processes differentially regulate APP processing, with some mechanisms favouring production of certain peptide species over others. For example, synaptic transmission having a bias towards regulating Aβ40 production over Aβ42 as well as processes involved in insulin and pancreatic biology having a bias for sAPPβ production over sAPPα. In addition, some of the pathways identified as regulators of APP processing contain genes (CLU, BIN1, CR1, PICALM, TREM2, SORL1, MEF2C, DSG2, EPH1A) recently implicated with AD through genome wide association studies (GWAS) and associated meta-analysis. In addition, we provide supporting evidence and a deeper mechanistic understanding of the role of diabetes in AD. The identification of these processes/pathways, their differential impact on APP processing, and their relationships to each other, provide a comprehensive systems biology view of the “regulatory landscape” of APP. PMID:25723573

BioNetSim: a Petri net-based modeling tool for simulations of biochemical processes.

PubMed

Gao, Junhui; Li, Li; Wu, Xiaolin; Wei, Dong-Qing

2012-03-01

BioNetSim, a Petri net-based software for modeling and simulating biochemistry processes, is developed, whose design and implement are presented in this paper, including logic construction, real-time access to KEGG (Kyoto Encyclopedia of Genes and Genomes), and BioModel database. Furthermore, glycolysis is simulated as an example of its application. BioNetSim is a helpful tool for researchers to download data, model biological network, and simulate complicated biochemistry processes. Gene regulatory networks, metabolic pathways, signaling pathways, and kinetics of cell interaction are all available in BioNetSim, which makes modeling more efficient and effective. Similar to other Petri net-based softwares, BioNetSim does well in graphic application and mathematic construction. Moreover, it shows several powerful predominances. (1) It creates models in database. (2) It realizes the real-time access to KEGG and BioModel and transfers data to Petri net. (3) It provides qualitative analysis, such as computation of constants. (4) It generates graphs for tracing the concentration of every molecule during the simulation processes.

Meeting the challenges of medical countermeasure development

PubMed Central

Maher, Carmen; Hu‐Primmer, Jean; MacGill, Tracy; Courtney, Brooke; Borio, Luciana

2012-01-01

Summary Despite substantial investments since the events of 2001, much work remains to prepare the nation for a chemical, biological, radiological or nuclear (CBRN) attack or to respond to an emerging infectious disease threat. Following a 2010 review of the US Public Health Emergency Medical Countermeasures Enterprise, FDA launched its Medical Countermeasures initiative (MCMi) to facilitate the development and availability of medical products to counter CBRN and emerging disease threats. As a regulatory agency, FDA has a unique and critical part to play in this national undertaking. Using a three‐pillar approach, FDA is addressing key challenges associated with the regulatory review process for medical countermeasures; gaps in regulatory science for MCM development and evaluation; and issues related to the legal, regulatory and policy framework for an effective public health response. Filling the gaps in the MCM Enterprise is a huge national undertaking, requiring the collaboration of all stakeholders, including federal partners, current and prospective developers of medical countermeasures, relevant research organizations, and state and local responders. Especially critical to success are an appreciation of the long timelines, risks and high costs associated with developing medical countermeasures – and the systems to deliver them – and the requisite support of all stakeholders, including national leadership. PMID:22925432

Regulatory aspects in the pharmaceutical development of nanoparticle drug delivery systems designed to cross the intestinal epithelium and M-cells.

PubMed

Hussain, Nasir

2016-11-30

This article reviews the field of oral uptake of nanoparticles across the gastrointestinal epithelium for the period 2006-2016. Analysis is conducted from the viewpoint of i) M-cell genetics and model development, ii) drug targeting to Peyer's patches and M-cells, and iii) physicochemical interactions of nanoparticles in the intestinal milieu. In light of these recent developments, regulatory considerations in the development of orally-absorbable nanoparticle drug products are discussed and focused on Module 3.2.P sub-sections of the Common Technical Document. Particular attention is paid to novel excipients, ligands and the non-standard method of manufacture. The novelty of this drug delivery system demands not only a multi-disciplinary scientific and regulatory approach but also a risk-adjusted consideration for a system defined by both processes and specifications. Given the current state of scientific development in the field it is suggested (in the author's personal opinion) that the design of nanoparticulate drug delivery systems should be kept as simple as possible (from a regulatory and manufacturing perspective) and to target the entire gastrointestinal epithelium. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

CLARA: an integrated clinical research administration system.

PubMed

Bian, Jiang; Xie, Mengjun; Hogan, William; Hutchins, Laura; Topaloglu, Umit; Lane, Cheryl; Holland, Jennifer; Wells, Thomas

2014-10-01

Administration of human subject research is complex, involving not only the institutional review board but also many other regulatory and compliance entities within a research enterprise. Its efficiency has a direct and substantial impact on the conduct and management of clinical research. In this paper, we report on the Clinical Research Administration (CLARA) platform developed at the University of Arkansas for Medical Sciences. CLARA is a comprehensive web-based system that can streamline research administrative tasks such as submissions, reviews, and approval processes for both investigators and different review committees on a single integrated platform. CLARA not only helps investigators to meet regulatory requirements but also provides tools for managing other clinical research activities including budgeting, contracting, and participant schedule planning. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Bioattractors: dynamical systems theory and the evolution of regulatory processes.

PubMed

Jaeger, Johannes; Monk, Nick

2014-06-01

In this paper, we illustrate how dynamical systems theory can provide a unifying conceptual framework for evolution of biological regulatory systems. Our argument is that the genotype-phenotype map can be characterized by the phase portrait of the underlying regulatory process. The features of this portrait--such as attractors with associated basins and their bifurcations--define the regulatory and evolutionary potential of a system. We show how the geometric analysis of phase space connects Waddington's epigenetic landscape to recent computational approaches for the study of robustness and evolvability in network evolution. We discuss how the geometry of phase space determines the probability of possible phenotypic transitions. Finally, we demonstrate how the active, self-organizing role of the environment in phenotypic evolution can be understood in terms of dynamical systems concepts. This approach yields mechanistic explanations that go beyond insights based on the simulation of evolving regulatory networks alone. Its predictions can now be tested by studying specific, experimentally tractable regulatory systems using the tools of modern systems biology. A systematic exploration of such systems will enable us to understand better the nature and origin of the phenotypic variability, which provides the substrate for evolution by natural selection. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

GMOs in animal agriculture: time to consider both costs and benefits in regulatory evaluations.

PubMed

Van Eenennaam, Alison L

2013-09-25

In 2012, genetically engineered (GE) crops were grown by 17.3 million farmers on over 170 million hectares. Over 70% of harvested GE biomass is fed to food producing animals, making them the major consumers of GE crops for the past 15 plus years. Prior to commercialization, GE crops go through an extensive regulatory evaluation. Over one hundred regulatory submissions have shown compositional equivalence, and comparable levels of safety, between GE crops and their conventional counterparts. One component of regulatory compliance is whole GE food/feed animal feeding studies. Both regulatory studies and independent peer-reviewed studies have shown that GE crops can be safely used in animal feed, and rDNA fragments have never been detected in products (e.g. milk, meat, eggs) derived from animals that consumed GE feed. Despite the fact that the scientific weight of evidence from these hundreds of studies have not revealed unique risks associated with GE feed, some groups are calling for more animal feeding studies, including long-term rodent studies and studies in target livestock species for the approval of GE crops. It is an opportune time to review the results of such studies as have been done to date to evaluate the value of the additional information obtained. Requiring long-term and target animal feeding studies would sharply increase regulatory compliance costs and prolong the regulatory process associated with the commercialization of GE crops. Such costs may impede the development of feed crops with enhanced nutritional characteristics and durability, particularly in the local varieties in small and poor developing countries. More generally it is time for regulatory evaluations to more explicitly consider both the reasonable and unique risks and benefits associated with the use of both GE plants and animals in agricultural systems, and weigh them against those associated with existing systems, and those of regulatory inaction. This would represent a shift away from a GE evaluation process that currently focuses only on risk assessment and identifying ever diminishing marginal hazards, to a regulatory approach that more objectively evaluates and communicates the likely impact of approving a new GE plant or animal on agricultural production systems.

GMOs in animal agriculture: time to consider both costs and benefits in regulatory evaluations

PubMed Central

2013-01-01

In 2012, genetically engineered (GE) crops were grown by 17.3 million farmers on over 170 million hectares. Over 70% of harvested GE biomass is fed to food producing animals, making them the major consumers of GE crops for the past 15 plus years. Prior to commercialization, GE crops go through an extensive regulatory evaluation. Over one hundred regulatory submissions have shown compositional equivalence, and comparable levels of safety, between GE crops and their conventional counterparts. One component of regulatory compliance is whole GE food/feed animal feeding studies. Both regulatory studies and independent peer-reviewed studies have shown that GE crops can be safely used in animal feed, and rDNA fragments have never been detected in products (e.g. milk, meat, eggs) derived from animals that consumed GE feed. Despite the fact that the scientific weight of evidence from these hundreds of studies have not revealed unique risks associated with GE feed, some groups are calling for more animal feeding studies, including long-term rodent studies and studies in target livestock species for the approval of GE crops. It is an opportune time to review the results of such studies as have been done to date to evaluate the value of the additional information obtained. Requiring long-term and target animal feeding studies would sharply increase regulatory compliance costs and prolong the regulatory process associated with the commercialization of GE crops. Such costs may impede the development of feed crops with enhanced nutritional characteristics and durability, particularly in the local varieties in small and poor developing countries. More generally it is time for regulatory evaluations to more explicitly consider both the reasonable and unique risks and benefits associated with the use of both GE plants and animals in agricultural systems, and weigh them against those associated with existing systems, and those of regulatory inaction. This would represent a shift away from a GE evaluation process that currently focuses only on risk assessment and identifying ever diminishing marginal hazards, to a regulatory approach that more objectively evaluates and communicates the likely impact of approving a new GE plant or animal on agricultural production systems. PMID:24066781

Electricity pricing policy: A neo-institutional, developmental and cross-national policy design map

NASA Astrophysics Data System (ADS)

Koundinya, Sridarshan Umesh

This dissertation explores the role of ideas and ideology in the mental policy design maps of regulators in the US and in India. The research approach is to describe the regulatory design process in the history of the US electric industry from a neo-institutional and developmental perspective. And then to use the insights of such a study to suggest policy options to a sample of Indian experts. A regulatory process model explores the interactions among normative values, regulatory instruments and historical phases in policy design. A spectrum of seven regulatory instruments--subsidized rates, average cost pricing, marginal cost pricing, time-of-use pricing, ramsey pricing, incentive regulation and spot pricing is examined. A neo-institutional perspective characterizes the process of institutionalizing these regulatory instruments as a design process that infuses them with values beyond mere technical requirements. The process model includes normative values such as efficiency, fairness, free choice and political feasibility. These values arise from an analytical classification of various market metaphors debated in the history of economic thought. The theory of development and co-evolution applied to the history of electricity regulation yields a typology of evolutionary phases in the US. The typology describes hierarchically emergent relationships between supply and demand and among the normative values. The theory hypothesizes technologically contingent relationships between pricing policies and normative values in the historical phases of dependence (or rural), independence (or urban) and interdependence (or informational). The contents of this model are represented as related elements in a policy design map that simplifies the process of designing regulatory instruments in the US. This neo-institutional, developmental policy design map was used to design a survey instrument. The survey was conducted among electricity experts in India to test the hypothesized inter-relationships among various elements at different levels of the policy design map in a cross-national context. The study adds value with a comprehensive design map that helps to organize and give coherence to the policy prescriptions made by Indian experts as they converge on one institutional model. Thus the dissertation contributes to the transfer of knowledge about regulatory practice from the US to India.

The BioDyn facility on ISS: Advancing biomaterial production in microgravity for commercial applications

NASA Astrophysics Data System (ADS)

Myers, Niki; Wessling, Francis; Deuser, Mark; Anderson, C. D.; Lewis, Marian

1999-01-01

The primary goals of the BioDyn program are to foster use of the microgravity environment for commercial production of bio-materials from cells, and to develop services and processes for obtaining these materials through space processing. The scope of products includes commercial bio-molecules such as cytokines, other cell growth regulatory proteins, hormones, monoclonal antibodies and enzymes; transplantable cells or tissues which can be improved by low-G processes, or which cannot be obtained through standard processes in earth gravity; agriculture biotechnology products from plant cells; microencapsulation for diabetes treatment; and factors regulating cellular aging. To facilitate BioDyn's commercial science driven goals, hardware designed for ISS incorporates the flexibility for interchange between the different ISS facilities including the glovebox, various thermal units and centrifuges. By providing a permanent research facility, ISS is the critical space-based platform required by scientists for carrying out the long-term experiments necessary for developing bio-molecules and tissues using several cell culture modalities including suspension and anchorage-dependent cell types.

Trust-based environmental regulation.

PubMed

Lange, Bettina; Gouldson, Andy

2010-10-15

Within this paper, we examine the contribution that trust-based relationships can make to achieving better-and particularly more effective, efficient and equitable-environmental regulation. While levels of trust in regulators, regulatory processes and outcomes are often discussed, the influence of trust on different actors and on different measures of regulatory performance is poorly understood. Within this paper, we define trust-based environmental regulation as a specific regulatory style that involves openness and cooperation in interaction between regulated, regulators and third-party stakeholders in order to achieve environmental protection objectives. We then discuss the pros and cons of trust relationships between regulators, regulated businesses and citizens for achieving behavioural change towards greater environmental protection. To illustrate the significance of these issues, we then examine three forms of contractual regulatory style where trust relationships are critically important: responsive regulation, self-regulation and environmental agreements. Based on this analysis, we highlight the importance of trust-based relationships, and we argue that one of the greatest contributions of trust-based environmental regulation is to challenge how we think about regulation. Trust is often understood as enabling existing regulatory relationships or in the case of self-regulation as a complement to regulation. However, we argue that the real potential of trust is to open up new ways for participants in regulatory regimes to engage in collective action, to go beyond a perception of regulation as driven by the competing interests of individual actors, and thus, to open up new channels of influence for behavioural change towards greater environmental protection. Our analysis therefore has great relevance for future research and for on-going debates on the future of regulation. Copyright © 2010. Published by Elsevier B.V.

Regulatory Challenges for Cartilage Repair Technologies.

PubMed

McGowan, Kevin B; Stiegman, Glenn

2013-01-01

In the United States, few Food and Drug Administration (FDA)-approved options exist for the treatment of focal cartilage and osteochondral lesions. Developers of products for cartilage repair face many challenges to obtain marketing approval from the FDA. The objective of this review is to discuss the necessary steps for FDA application and approval for a new cartilage repair product. FDA Guidance Documents, FDA Panel Meetings, scientific organization recommendations, and clinicaltrials.gov were reviewed to demonstrate the current thinking of FDA and the scientific community on the regulatory process for cartilage repair therapies. Cartilage repair therapies can receive market approval from FDA as medical devices, drugs, or biologics, and the specific classification of product can affect the nonclinical, clinical, and regulatory strategy to bring the product to market. Recent FDA guidance gives an outline of the required elements to bring a cartilage repair product to market, although these standards are often very general. As a result, companies have to carefully craft their study patient population, comparator group, and clinical endpoint to best showcase their product's attributes. In addition, regulatory strategy and manufacturing process validation need to be considered early in the clinical study process to allow for timely product approval following the completion of clinical study. Although the path to regulatory approval for a cartilage repair therapy is challenging and time-consuming, proper clinical trial planning and attention to the details can eventually save companies time and money by bringing a product to the market in the most expeditious process possible.

Regulatory Challenges for Cartilage Repair Technologies

PubMed Central

Stiegman, Glenn

2013-01-01

In the United States, few Food and Drug Administration (FDA)–approved options exist for the treatment of focal cartilage and osteochondral lesions. Developers of products for cartilage repair face many challenges to obtain marketing approval from the FDA. The objective of this review is to discuss the necessary steps for FDA application and approval for a new cartilage repair product. FDA Guidance Documents, FDA Panel Meetings, scientific organization recommendations, and clinicaltrials.gov were reviewed to demonstrate the current thinking of FDA and the scientific community on the regulatory process for cartilage repair therapies. Cartilage repair therapies can receive market approval from FDA as medical devices, drugs, or biologics, and the specific classification of product can affect the nonclinical, clinical, and regulatory strategy to bring the product to market. Recent FDA guidance gives an outline of the required elements to bring a cartilage repair product to market, although these standards are often very general. As a result, companies have to carefully craft their study patient population, comparator group, and clinical endpoint to best showcase their product’s attributes. In addition, regulatory strategy and manufacturing process validation need to be considered early in the clinical study process to allow for timely product approval following the completion of clinical study. Although the path to regulatory approval for a cartilage repair therapy is challenging and time-consuming, proper clinical trial planning and attention to the details can eventually save companies time and money by bringing a product to the market in the most expeditious process possible. PMID:26069647

Incorporating the patient experience into regulatory decision making in the USA, Europe, and Canada.

PubMed

Kluetz, Paul G; O'Connor, Daniel J; Soltys, Katherine

2018-05-01

The clinical development of cancer therapeutics is a global undertaking, and incorporation of the patient experience into the clinical decision-making process is of increasing interest to the international regulatory and health policy community. Disease and treatment-related symptoms and their effect on patient function and health-related quality of life are important outcomes to consider. The identification of methods to scientifically assess, analyse, interpret, and present these clinical outcomes requires sustained international collaboration by multiple stakeholders including patients, clinicians, scientists, and policy makers. Several data sources can be considered to capture the patient experience, including patient-reported outcome (PRO) measures, performance measures, wearable devices, and biosensors, as well as the careful collection and analysis of clinical events and supportive care medications. In this Policy Review, we focus on PRO measures and present the perspectives of three international regulatory scientists to identify areas of common ground regarding opportunities to incorporate rigorous PRO data into the regulatory decision-making process. Copyright © 2018 Elsevier Ltd. All rights reserved.

GRIL-Seq, a method for identifying direct targets of bacterial small regulatory RNA by in vivo proximity ligation

PubMed Central

Han, Kook; Tjaden, Brian; Lory, Stephen

2017-01-01

The first step in the post-transcriptional regulatory function of most bacterial small non-coding RNAs (sRNAs) is base-pairing with partially complementary sequences of targeted transcripts. We present a simple method for identifying sRNA targets in vivo and defining processing sites of the regulated transcripts. The technique (referred to as GRIL-Seq) is based on preferential ligation of sRNAs to ends of base-paired targets in bacteria co-expressing T4 RNA ligase, followed by sequencing to identify the chimeras. In addition to the RNA chaperone Hfq, the GRIL-Seq method depends on the activity of the pyrophosphorylase RppH. Using PrrF1, an iron-regulated sRNA in Pseudomonas aeruginosa, we demonstrate that direct regulatory targets of this sRNA can be readily identified. Therefore, GRIL-Seq represents a powerful tool not only for identifying direct targets of sRNAs in a variety of environments, but can also result in uncovering novel roles for sRNAs and their targets in complex regulatory networks. PMID:28005055

GRIL-seq provides a method for identifying direct targets of bacterial small regulatory RNA by in vivo proximity ligation.

PubMed

Han, Kook; Tjaden, Brian; Lory, Stephen

2016-12-22

The first step in the post-transcriptional regulatory function of most bacterial small non-coding RNAs (sRNAs) is base pairing with partially complementary sequences of targeted transcripts. We present a simple method for identifying sRNA targets in vivo and defining processing sites of the regulated transcripts. The technique, referred to as global small non-coding RNA target identification by ligation and sequencing (GRIL-seq), is based on preferential ligation of sRNAs to the ends of base-paired targets in bacteria co-expressing T4 RNA ligase, followed by sequencing to identify the chimaeras. In addition to the RNA chaperone Hfq, the GRIL-seq method depends on the activity of the pyrophosphorylase RppH. Using PrrF1, an iron-regulated sRNA in Pseudomonas aeruginosa, we demonstrated that direct regulatory targets of this sRNA can readily be identified. Therefore, GRIL-seq represents a powerful tool not only for identifying direct targets of sRNAs in a variety of environments, but also for uncovering novel roles for sRNAs and their targets in complex regulatory networks.

Solid-state chemistry and particle engineering with supercritical fluids in pharmaceutics.

PubMed

Pasquali, Irene; Bettini, Ruggero; Giordano, Ferdinando

2006-03-01

The present commentary aims to review the modern and innovative strategies in particle engineering by the supercritical fluid technologies and it is principally concerned with the aspects of solid-state chemistry. Supercritical fluids based processes for particle production have been proved suitable for controlling solid-state, morphology and particle size of pharmaceuticals, in some cases on an industrial scale. Supercritical fluids should be considered in a prominent position in the development processes of drug products for the 21st century. In this respect, this innovative technology will help in meeting the more and more stringent requirements of regulatory authorities in terms of solid-state characterisation and purity, and environmental acceptability.

Developing a Third-Party Analytics Application Using Australia’s National Personal Health Records System: Case Study

PubMed Central

van Kasteren, Yasmin; Musiat, Peter; Kidd, Michael

2018-01-01

Background My Health Record (MyHR) is Australia’s national electronic health record (EHR) system. Poor usability and functionality have resulted in low utility, affecting enrollment and participation rates by both patients and clinicians alike. Similar to apps on mobile phone app stores, innovative third-party applications of MyHR platform data can enhance the usefulness of the platform, but there is a paucity of research into the processes involved in developing third-party applications that integrate and use data from EHR systems. Objective The research describes the challenges involved in pioneering the development of a patient and clinician Web-based software application for MyHR and insights resulting from this experience. Methods This research uses a case study approach, investigating the development and implementation of Actionable Intime Insights (AI2), a third-party application for MyHR, which translates Medicare claims records stored in MyHR into a clinically meaningful timeline visualization of health data for both patients and clinicians. This case study identifies the challenges encountered by the Personal Health Informatics team from Flinders University in the MyHR third-party application development environment. Results The study presents a nuanced understanding of different data types and quality of data in MyHR and the complexities associated with developing secondary-use applications. Regulatory requirements associated with utilization of MyHR data, restrictions on visualizations of data, and processes of testing third-party applications were encountered during the development of the application. Conclusions This study identified several processes, technical and regulatory barriers which, if addressed, can make MyHR a thriving ecosystem of health applications. It clearly identifies opportunities and considerations for the Australian Digital Health Agency and other national bodies wishing to encourage the development of new and innovative use cases for national EHRs. PMID:29691211

Developing a Third-Party Analytics Application Using Australia's National Personal Health Records System: Case Study.

PubMed

Bidargaddi, Niranjan; van Kasteren, Yasmin; Musiat, Peter; Kidd, Michael

2018-04-24

My Health Record (MyHR) is Australia's national electronic health record (EHR) system. Poor usability and functionality have resulted in low utility, affecting enrollment and participation rates by both patients and clinicians alike. Similar to apps on mobile phone app stores, innovative third-party applications of MyHR platform data can enhance the usefulness of the platform, but there is a paucity of research into the processes involved in developing third-party applications that integrate and use data from EHR systems. The research describes the challenges involved in pioneering the development of a patient and clinician Web-based software application for MyHR and insights resulting from this experience. This research uses a case study approach, investigating the development and implementation of Actionable Intime Insights (AI 2 ), a third-party application for MyHR, which translates Medicare claims records stored in MyHR into a clinically meaningful timeline visualization of health data for both patients and clinicians. This case study identifies the challenges encountered by the Personal Health Informatics team from Flinders University in the MyHR third-party application development environment. The study presents a nuanced understanding of different data types and quality of data in MyHR and the complexities associated with developing secondary-use applications. Regulatory requirements associated with utilization of MyHR data, restrictions on visualizations of data, and processes of testing third-party applications were encountered during the development of the application. This study identified several processes, technical and regulatory barriers which, if addressed, can make MyHR a thriving ecosystem of health applications. It clearly identifies opportunities and considerations for the Australian Digital Health Agency and other national bodies wishing to encourage the development of new and innovative use cases for national EHRs. ©Niranjan Bidargaddi, Yasmin van Kasteren, Peter Musiat, Michael Kidd. Originally published in JMIR Medical Informatics (http://medinform.jmir.org), 24.04.2018.

Proteomic analysis of maize grain development using iTRAQ reveals temporal programs of diverse metabolic processes.

PubMed

Yu, Tao; Li, Geng; Dong, Shuting; Liu, Peng; Zhang, Jiwang; Zhao, Bin

2016-11-04

Grain development in maize is an essential process in the plant's life cycle and is vital for use of the plant as a crop for animals and humans. However, little is known regarding the protein regulatory networks that control grain development. Here, isobaric tag for relative and absolute quantification (iTRAQ) technology was used to analyze temporal changes in protein expression during maize grain development. Maize grain proteins and changes in protein expression at eight developmental stages from 3 to 50 d after pollination (DAP) were performed using iTRAQ-based proteomics. Overall, 4751 proteins were identified; 2639 of these were quantified and 1235 showed at least 1.5-fold changes in expression levels at different developmental stages and were identified as differentially expressed proteins (DEPs). The DEPs were involved in different cellular and metabolic processes with a preferential distribution to protein synthesis/destination and metabolism categories. A K-means clustering analysis revealed coordinated protein expression associated with different functional categories/subcategories at different development stages. Our results revealed developing maize grain display different proteomic characteristics at distinct stages, such as numerous DEPs for cell growth/division were highly expressed during early stages, whereas those for starch biosynthesis and defense/stress accumulated in middle and late stages, respectively. We also observed coordinated expression of multiple proteins of the antioxidant system, which are essential for the maintenance of reactive oxygen species (ROS) homeostasis during grain development. Particularly, some DEPs, such as zinc metallothionein class II, pyruvate orthophosphate dikinase (PPDK) and 14-3-3 proteins, undergo major changes in expression at specific developmental stages, suggesting their roles in maize grain development. These results provide a valuable resource for analyzing protein function on a global scale and also provide new insights into the potential protein regulatory networks that control grain yield and quality.

Waste management technology development and demonstration programs at Brookhaven National Laboratory

NASA Technical Reports Server (NTRS)

Kalb, Paul D.; Colombo, Peter

1991-01-01

Two thermoplastic processes for improved treatment of radioactive, hazardous, and mixed wastes were developed from bench scale through technology demonstration: polyethylene encapsulation and modified sulfur cement encapsulation. The steps required to bring technologies from the research and development stage through full scale implementation are described. Both systems result in durable waste forms that meet current Nuclear Regulatory Commission and Environmental Protection Agency regulatory criteria and provide significant improvements over conventional solidification systems such as hydraulic cement. For example, the polyethylene process can encapsulate up to 70 wt pct. nitrate salt, compared with a maximum of about 20 wt pct. for the best hydraulic cement formulation. Modified sulfur cement waste forms containing as much as 43 wt pct. incinerator fly ash were formulated, whereas the maximum quantity of this waste in hydraulic cement is 16 wt pct.

DREISS: Using State-Space Models to Infer the Dynamics of Gene Expression Driven by External and Internal Regulatory Networks

PubMed Central

Gerstein, Mark

2016-01-01

Gene expression is controlled by the combinatorial effects of regulatory factors from different biological subsystems such as general transcription factors (TFs), cellular growth factors and microRNAs. A subsystem’s gene expression may be controlled by its internal regulatory factors, exclusively, or by external subsystems, or by both. It is thus useful to distinguish the degree to which a subsystem is regulated internally or externally–e.g., how non-conserved, species-specific TFs affect the expression of conserved, cross-species genes during evolution. We developed a computational method (DREISS, dreiss.gerteinlab.org) for analyzing the Dynamics of gene expression driven by Regulatory networks, both External and Internal based on State Space models. Given a subsystem, the “state” and “control” in the model refer to its own (internal) and another subsystem’s (external) gene expression levels. The state at a given time is determined by the state and control at a previous time. Because typical time-series data do not have enough samples to fully estimate the model’s parameters, DREISS uses dimensionality reduction, and identifies canonical temporal expression trajectories (e.g., degradation, growth and oscillation) representing the regulatory effects emanating from various subsystems. To demonstrate capabilities of DREISS, we study the regulatory effects of evolutionarily conserved vs. divergent TFs across distant species. In particular, we applied DREISS to the time-series gene expression datasets of C. elegans and D. melanogaster during their embryonic development. We analyzed the expression dynamics of the conserved, orthologous genes (orthologs), seeing the degree to which these can be accounted for by orthologous (internal) versus species-specific (external) TFs. We found that between two species, the orthologs have matched, internally driven expression patterns but very different externally driven ones. This is particularly true for genes with evolutionarily ancient functions (e.g. the ribosomal proteins), in contrast to those with more recently evolved functions (e.g., cell-cell communication). This suggests that despite striking morphological differences, some fundamental embryonic-developmental processes are still controlled by ancient regulatory systems. PMID:27760135

DREISS: Using State-Space Models to Infer the Dynamics of Gene Expression Driven by External and Internal Regulatory Networks.

PubMed

Wang, Daifeng; He, Fei; Maslov, Sergei; Gerstein, Mark

2016-10-01

Gene expression is controlled by the combinatorial effects of regulatory factors from different biological subsystems such as general transcription factors (TFs), cellular growth factors and microRNAs. A subsystem's gene expression may be controlled by its internal regulatory factors, exclusively, or by external subsystems, or by both. It is thus useful to distinguish the degree to which a subsystem is regulated internally or externally-e.g., how non-conserved, species-specific TFs affect the expression of conserved, cross-species genes during evolution. We developed a computational method (DREISS, dreiss.gerteinlab.org) for analyzing the Dynamics of gene expression driven by Regulatory networks, both External and Internal based on State Space models. Given a subsystem, the "state" and "control" in the model refer to its own (internal) and another subsystem's (external) gene expression levels. The state at a given time is determined by the state and control at a previous time. Because typical time-series data do not have enough samples to fully estimate the model's parameters, DREISS uses dimensionality reduction, and identifies canonical temporal expression trajectories (e.g., degradation, growth and oscillation) representing the regulatory effects emanating from various subsystems. To demonstrate capabilities of DREISS, we study the regulatory effects of evolutionarily conserved vs. divergent TFs across distant species. In particular, we applied DREISS to the time-series gene expression datasets of C. elegans and D. melanogaster during their embryonic development. We analyzed the expression dynamics of the conserved, orthologous genes (orthologs), seeing the degree to which these can be accounted for by orthologous (internal) versus species-specific (external) TFs. We found that between two species, the orthologs have matched, internally driven expression patterns but very different externally driven ones. This is particularly true for genes with evolutionarily ancient functions (e.g. the ribosomal proteins), in contrast to those with more recently evolved functions (e.g., cell-cell communication). This suggests that despite striking morphological differences, some fundamental embryonic-developmental processes are still controlled by ancient regulatory systems.

Promoting Adoption of the 3Rs through Regulatory Qualification.

PubMed

Walker, Elizabeth Gribble; Baker, Amanda F; Sauer, John-Michael

2016-12-01

One mechanism to advance the application of novel safety assessment methodologies in drug development, including in silico or in vitro approaches that reduce the use of animals in toxicology studies, is regulatory qualification. Regulatory qualification, a formal process defined at the the U. S. Food and Drug Administration and the European Medicines Agency, hinges on a central concept of stating an appropriate "context of use" for a novel drug development tool (DDT) that precisely defines how that DDT can be used to support decision making in a regulated drug development setting. When accumulating the data to support a particular "context-of-use," the concept of "fit-for-purpose" often guides assay validation, as well as the type and amount of data or evidence required to evaluate the tool. This paper will review pathways for regulatory acceptance of novel DDTs and discuss examples of safety projects considered for regulatory qualification. Key concepts to be considered when defining the evidence required to formally adopt and potentially replace animal-intensive traditional safety assessment methods using qualified DDTs are proposed. Presently, the use of qualified translational kidney safety biomarkers can refine and reduce the total numbers of animals used in drug development. We propose that the same conceptual regulatory framework will be appropriate to assess readiness of new technologies that may eventually replace whole animal models. © The Author 2016. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Peer Review for EPA's Biologically Based Dose-Response ...

EPA Pesticide Factsheets

EPA is developing a regulation for perchlorate in drinking water. As part the regulatory process EPA must develop a Maximum Contaminant Level Goal (MCLG). FDA and EPA scientists developed a biologically based dose-response (BBDR) model to assist in deriving the MCLG. This model is designed to determine under what conditions of iodine nutrition and exposure to perchlorate across sensitive lifestages would result in low serum free and total thyroxine (hypothyroxinemia). EPA is undertaking a peer review to provide a focused, objective independent peer evaluation of the draft model and its model results report. EPA is undertaking a peer review to provide a focused, objective independent peer evaluation of the draft model and its model results report. Peer review is an important component of the scientific process. The criticism, suggestions, and new ideas provided by the peer reviewers stimulate creative thought, strengthen the interpretation of the reviewed material, and confer credibility on the product. The peer review objective is to provide advice to EPA on steps that will yield a highly credible scientific product that is supported by the scientific community and a defensible perchlorate MCLG.

A Machine Learning Approach to Predict Gene Regulatory Networks in Seed Development in Arabidopsis

PubMed Central

Ni, Ying; Aghamirzaie, Delasa; Elmarakeby, Haitham; Collakova, Eva; Li, Song; Grene, Ruth; Heath, Lenwood S.

2016-01-01

Gene regulatory networks (GRNs) provide a representation of relationships between regulators and their target genes. Several methods for GRN inference, both unsupervised and supervised, have been developed to date. Because regulatory relationships consistently reprogram in diverse tissues or under different conditions, GRNs inferred without specific biological contexts are of limited applicability. In this report, a machine learning approach is presented to predict GRNs specific to developing Arabidopsis thaliana embryos. We developed the Beacon GRN inference tool to predict GRNs occurring during seed development in Arabidopsis based on a support vector machine (SVM) model. We developed both global and local inference models and compared their performance, demonstrating that local models are generally superior for our application. Using both the expression levels of the genes expressed in developing embryos and prior known regulatory relationships, GRNs were predicted for specific embryonic developmental stages. The targets that are strongly positively correlated with their regulators are mostly expressed at the beginning of seed development. Potential direct targets were identified based on a match between the promoter regions of these inferred targets and the cis elements recognized by specific regulators. Our analysis also provides evidence for previously unknown inhibitory effects of three positive regulators of gene expression. The Beacon GRN inference tool provides a valuable model system for context-specific GRN inference and is freely available at https://github.com/BeaconProjectAtVirginiaTech/beacon_network_inference.git. PMID:28066488

MapReduce Algorithms for Inferring Gene Regulatory Networks from Time-Series Microarray Data Using an Information-Theoretic Approach.

PubMed

Abduallah, Yasser; Turki, Turki; Byron, Kevin; Du, Zongxuan; Cervantes-Cervantes, Miguel; Wang, Jason T L

2017-01-01

Gene regulation is a series of processes that control gene expression and its extent. The connections among genes and their regulatory molecules, usually transcription factors, and a descriptive model of such connections are known as gene regulatory networks (GRNs). Elucidating GRNs is crucial to understand the inner workings of the cell and the complexity of gene interactions. To date, numerous algorithms have been developed to infer gene regulatory networks. However, as the number of identified genes increases and the complexity of their interactions is uncovered, networks and their regulatory mechanisms become cumbersome to test. Furthermore, prodding through experimental results requires an enormous amount of computation, resulting in slow data processing. Therefore, new approaches are needed to expeditiously analyze copious amounts of experimental data resulting from cellular GRNs. To meet this need, cloud computing is promising as reported in the literature. Here, we propose new MapReduce algorithms for inferring gene regulatory networks on a Hadoop cluster in a cloud environment. These algorithms employ an information-theoretic approach to infer GRNs using time-series microarray data. Experimental results show that our MapReduce program is much faster than an existing tool while achieving slightly better prediction accuracy than the existing tool.

Validation of gamma irradiator controls for quality and regulatory compliance

NASA Astrophysics Data System (ADS)

Harding, Rorry B.; Pinteric, Francis J. A.

1995-09-01

Since 1978 the U.S. Food and Drug Administration (FDA) has had both the legal authority and the Current Good Manufacturing Practice (CGMP) regulations in place to require irradiator owners who process medical devices to produce evidence of Irradiation Process Validation. One of the key components of Irradiation Process Validation is the validation of the irradiator controls. However, it is only recently that FDA audits have focused on this component of the process validation. What is Irradiator Control System Validation? What constitutes evidence of control? How do owners obtain evidence? What is the irradiator supplier's role in validation? How does the ISO 9000 Quality Standard relate to the FDA's CGMP requirement for evidence of Control System Validation? This paper presents answers to these questions based on the recent experiences of Nordion's engineering and product management staff who have worked with several US-based irradiator owners. This topic — Validation of Irradiator Controls — is a significant regulatory compliance and operations issue within the irradiator suppliers' and users' community.

Adaptive Equilibrium Regulation: A Balancing Act in Two Timescales

PubMed Central

Boker, Steven M.

2015-01-01

An equilibrium involves a balancing of forces. Just as one maintains upright posture in standing or walking, many self-regulatory and interpersonal behaviors can be framed as a balancing act between an ever changing environment and within-person processes. The emerging balance between person and environment, the equilibria, are dynamic and adaptive in response to development and learning. A distinction is made between equilibrium achieved solely due to a short timescale balancing of forces and a longer timescale preferred equilibrium which we define as a state towards which the system slowly adapts. Together, these are developed into a framework that this article calls Adaptive Equilibrium Regulation (ÆR), which separates a regulatory process into two timescales: a faster regulation that automatically balances forces and a slower timescale adaptation process that reconfigures the fast regulation so as to move the system towards its preferred equilibrium when an environmental force persists over the longer timescale. This way of thinking leads to novel models for the interplay between multiple timescales of behavior, learning, and development. PMID:27066197

Design of clinical trials for therapeutic cancer vaccines development.

PubMed

Mackiewicz, Jacek; Mackiewicz, Andrzej

2009-12-25

Advances in molecular and cellular biology as well as biotechnology led to definition of a group of drugs referred to as medicinal products of advanced technologies. It includes gene therapy products, somatic cell therapeutics and tissue engineering. Therapeutic cancer vaccines including whole cell tumor cells vaccines or gene modified whole cells belong to somatic therapeutics and/or gene therapy products category. The drug development is a multistep complex process. It comprises of two phases: preclinical and clinical. Guidelines on preclinical testing of cell based immunotherapy medicinal products have been defined by regulatory agencies and are available. However, clinical testing of therapeutic cancer vaccines is still under debate. It presents a serious problem since recently clinical efficacy of the number of cancer vaccines has been demonstrated that focused a lot of public attention. In general clinical testing in the current form is very expensive, time consuming and poorly designed what may lead to overlooking of products clinically beneficial for patients. Accordingly regulatory authorities and researches including Cancer Vaccine Clinical Trial Working Group proposed three regulatory solutions to facilitate clinical development of cancer vaccines: cost-recovery program, conditional marketing authorization, and a new development paradigm. Paradigm includes a model in which cancer vaccines are investigated in two types of clinical trials: proof-of-principle and efficacy. The proof-of-principle trial objectives are: safety; dose selection and schedule of vaccination; and demonstration of proof-of-principle. Efficacy trials are randomized clinical trials with objectives of demonstrating clinical benefit either directly or through a surrogate. The clinical end points are still under debate.

RNA-mediated regulation in Gram-positive pathogens: an overview punctuated with examples from the group A Streptococcus

PubMed Central

Miller, Eric W.; Cao, Tram N.; Pflughoeft, Kathryn J.; Sumby, Paul

2014-01-01

RNA-based mechanisms of regulation represent a ubiquitous class of regulators that are associated with diverse processes including nutrient sensing, stress response, modulation of horizontal gene transfer, and virulence factor expression. While better studied in Gram-negative bacteria, the literature is replete with examples of the importance of RNA-mediated regulatory mechanisms to the virulence and fitness of Gram-positives. Regulatory RNAs are classified as cis-acting, e.g. riboswitches, which modulate the transcription, translation, or stability of co-transcribed RNA, or trans-acting, e.g. small regulatory RNAs, which target separate mRNAs or proteins. The group A Streptococcus (GAS, Streptococcus pyogenes) is a Gram-positive bacterial pathogen from which several regulatory RNA mechanisms have been characterized. The study of RNA-mediated regulation in GAS has uncovered novel concepts with respect to how small regulatory RNAs may positively regulate target mRNA stability, and to how CRISPR RNAs are processed from longer precursors. This review provides an overview of RNA-mediated regulation in Gram-positive bacteria, and is highlighted with specific examples from GAS research. The key roles that these systems play in regulating bacterial virulence are discussed and future perspectives outlined. PMID:25091277

From Genes to Networks: Characterizing Gene-Regulatory Interactions in Plants.

PubMed

Kaufmann, Kerstin; Chen, Dijun

2017-01-01

Plants, like other eukaryotes, have evolved complex mechanisms to coordinate gene expression during development, environmental response, and cellular homeostasis. Transcription factors (TFs), accompanied by basic cofactors and posttranscriptional regulators, are key players in gene-regulatory networks (GRNs). The coordinated control of gene activity is achieved by the interplay of these factors and by physical interactions between TFs and DNA. Here, we will briefly outline recent technological progress made to elucidate GRNs in plants. We will focus on techniques that allow us to characterize physical interactions in GRNs in plants and to analyze their regulatory consequences. Targeted manipulation allows us to test the relevance of specific gene-regulatory interactions. The combination of genome-wide experimental approaches with mathematical modeling allows us to get deeper insights into key-regulatory interactions and combinatorial control of important processes in plants.

Application of ICH Q9 Quality Risk Management Tools for Advanced Development of Hot Melt Coated Multiparticulate Systems.

PubMed

Stocker, Elena; Becker, Karin; Hate, Siddhi; Hohl, Roland; Schiemenz, Wolfgang; Sacher, Stephan; Zimmer, Andreas; Salar-Behzadi, Sharareh

2017-01-01

This study aimed to apply quality risk management based on the The International Conference on Harmonisation guideline Q9 for the early development stage of hot melt coated multiparticulate systems for oral administration. N-acetylcysteine crystals were coated with a formulation composing tripalmitin and polysorbate 65. The critical quality attributes (CQAs) were initially prioritized using failure mode and effects analysis. The CQAs of the coated material were defined as particle size, taste-masking efficiency, and immediate release profile. The hot melt coated process was characterized via a flowchart, based on the identified potential critical process parameters (CPPs) and their impact on the CQAs. These CPPs were prioritized using a process failure mode, effects, and criticality analysis and their critical impact on the CQAs was experimentally confirmed using a statistical design of experiments. Spray rate, atomization air pressure, and air flow rate were identified as CPPs. Coating amount and content of polysorbate 65 in the coating formulation were identified as critical material attributes. A hazard and critical control points analysis was applied to define control strategies at the critical process points. A fault tree analysis evaluated causes for potential process failures. We successfully demonstrated that a standardized quality risk management approach optimizes the product development sustainability and supports the regulatory aspects. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Network-Based Methods for Identifying Key Active Proteins in the Extracellular Electron Transfer Process in Shewanella oneidensis MR-1.

PubMed

Ding, Dewu; Sun, Xiao

2018-01-16

Shewanella oneidensis MR-1 can transfer electrons from the intracellular environment to the extracellular space of the cells to reduce the extracellular insoluble electron acceptors (Extracellular Electron Transfer, EET). Benefiting from this EET capability, Shewanella has been widely used in different areas, such as energy production, wastewater treatment, and bioremediation. Genome-wide proteomics data was used to determine the active proteins involved in activating the EET process. We identified 1012 proteins with decreased expression and 811 proteins with increased expression when the EET process changed from inactivation to activation. We then networked these proteins to construct the active protein networks, and identified the top 20 key active proteins by network centralization analysis, including metabolism- and energy-related proteins, signal and transcriptional regulatory proteins, translation-related proteins, and the EET-related proteins. We also constructed the integrated protein interaction and transcriptional regulatory networks for the active proteins, then found three exclusive active network motifs involved in activating the EET process-Bi-feedforward Loop, Regulatory Cascade with a Feedback, and Feedback with a Protein-Protein Interaction (PPI)-and identified the active proteins involved in these motifs. Both enrichment analysis and comparative analysis to the whole-genome data implicated the multiheme c -type cytochromes and multiple signal processing proteins involved in the process. Furthermore, the interactions of these motif-guided active proteins and the involved functional modules were discussed. Collectively, by using network-based methods, this work reported a proteome-wide search for the key active proteins that potentially activate the EET process.

Thermodynamics-based models of transcriptional regulation with gene sequence.

PubMed

Wang, Shuqiang; Shen, Yanyan; Hu, Jinxing

2015-12-01

Quantitative models of gene regulatory activity have the potential to improve our mechanistic understanding of transcriptional regulation. However, the few models available today have been based on simplistic assumptions about the sequences being modeled or heuristic approximations of the underlying regulatory mechanisms. In this work, we have developed a thermodynamics-based model to predict gene expression driven by any DNA sequence. The proposed model relies on a continuous time, differential equation description of transcriptional dynamics. The sequence features of the promoter are exploited to derive the binding affinity which is derived based on statistical molecular thermodynamics. Experimental results show that the proposed model can effectively identify the activity levels of transcription factors and the regulatory parameters. Comparing with the previous models, the proposed model can reveal more biological sense.

Regulatory science based approach in development of novel medical devices.

PubMed

Sakuma, Ichiro

2015-08-01

For development rational evaluation method for medical devices' safety and efficacy, regulatory science studies are important. Studies on regulatory affairs related to a medical device under development should be conducted as well as its technological development. Clinical performance of a medical device is influenced by performance of the device, medical doctors' skill, pathological condition of a patient, and so on. Thus it is sometimes difficult to demonstrate superiority of the device in terms of clinical outcome although its efficacy as a medical device is accepted. Setting of appropriate end points is required to evaluate a medical device appropriately. Risk assessment and risk management are the basis of medical device safety assurance. In case of medical device software, there are difficulties in identifying the risk due to its complexity of user environment and different design and manufacturing procedure compared with conventional hardware based medical devices. Recent technological advancement such as information and communication technologies (ICT) for medical devices and wireless network has raised new issue on risk management: cybersecurity. We have to watch closely the progress of safety standard development.

How adverse outcome pathways can aid the development and use of computational prediction models for regulatory toxicology

EPA Science Inventory

Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumu...

MULTI-MEDIA MICROBIOLOGICAL RISK ASSESSMENT METHODOLOGY FOR MUNICIPAL WASTEWATER SLUDGES

EPA Science Inventory

In order to reduce the risk of municipal sludge to acceptable levels, the U.S. EPA has undertaken a regulatory program based on risk assessment and risk management. The key to such a program is the development of a methodology which allows the regulatory agency to quantify the re...

Predictive regulatory models in Drosophila melanogaster by integrative inference of transcriptional networks

PubMed Central

Marbach, Daniel; Roy, Sushmita; Ay, Ferhat; Meyer, Patrick E.; Candeias, Rogerio; Kahveci, Tamer; Bristow, Christopher A.; Kellis, Manolis

2012-01-01

Gaining insights on gene regulation from large-scale functional data sets is a grand challenge in systems biology. In this article, we develop and apply methods for transcriptional regulatory network inference from diverse functional genomics data sets and demonstrate their value for gene function and gene expression prediction. We formulate the network inference problem in a machine-learning framework and use both supervised and unsupervised methods to predict regulatory edges by integrating transcription factor (TF) binding, evolutionarily conserved sequence motifs, gene expression, and chromatin modification data sets as input features. Applying these methods to Drosophila melanogaster, we predict ∼300,000 regulatory edges in a network of ∼600 TFs and 12,000 target genes. We validate our predictions using known regulatory interactions, gene functional annotations, tissue-specific expression, protein–protein interactions, and three-dimensional maps of chromosome conformation. We use the inferred network to identify putative functions for hundreds of previously uncharacterized genes, including many in nervous system development, which are independently confirmed based on their tissue-specific expression patterns. Last, we use the regulatory network to predict target gene expression levels as a function of TF expression, and find significantly higher predictive power for integrative networks than for motif or ChIP-based networks. Our work reveals the complementarity between physical evidence of regulatory interactions (TF binding, motif conservation) and functional evidence (coordinated expression or chromatin patterns) and demonstrates the power of data integration for network inference and studies of gene regulation at the systems level. PMID:22456606

FALCON: a toolbox for the fast contextualization of logical networks

PubMed Central

De Landtsheer, Sébastien; Trairatphisan, Panuwat; Lucarelli, Philippe; Sauter, Thomas

2017-01-01

Abstract Motivation Mathematical modelling of regulatory networks allows for the discovery of knowledge at the system level. However, existing modelling tools are often computation-heavy and do not offer intuitive ways to explore the model, to test hypotheses or to interpret the results biologically. Results We have developed a computational approach to contextualize logical models of regulatory networks with biological measurements based on a probabilistic description of rule-based interactions between the different molecules. Here, we propose a Matlab toolbox, FALCON, to automatically and efficiently build and contextualize networks, which includes a pipeline for conducting parameter analysis, knockouts and easy and fast model investigation. The contextualized models could then provide qualitative and quantitative information about the network and suggest hypotheses about biological processes. Availability and implementation FALCON is freely available for non-commercial users on GitHub under the GPLv3 licence. The toolbox, installation instructions, full documentation and test datasets are available at https://github.com/sysbiolux/FALCON. FALCON runs under Matlab (MathWorks) and requires the Optimization Toolbox. Contact thomas.sauter@uni.lu Supplementary information Supplementary data are available at Bioinformatics online. PMID:28673016

FALCON: a toolbox for the fast contextualization of logical networks.

PubMed

De Landtsheer, Sébastien; Trairatphisan, Panuwat; Lucarelli, Philippe; Sauter, Thomas

2017-11-01

Mathematical modelling of regulatory networks allows for the discovery of knowledge at the system level. However, existing modelling tools are often computation-heavy and do not offer intuitive ways to explore the model, to test hypotheses or to interpret the results biologically. We have developed a computational approach to contextualize logical models of regulatory networks with biological measurements based on a probabilistic description of rule-based interactions between the different molecules. Here, we propose a Matlab toolbox, FALCON, to automatically and efficiently build and contextualize networks, which includes a pipeline for conducting parameter analysis, knockouts and easy and fast model investigation. The contextualized models could then provide qualitative and quantitative information about the network and suggest hypotheses about biological processes. FALCON is freely available for non-commercial users on GitHub under the GPLv3 licence. The toolbox, installation instructions, full documentation and test datasets are available at https://github.com/sysbiolux/FALCON. FALCON runs under Matlab (MathWorks) and requires the Optimization Toolbox. thomas.sauter@uni.lu. Supplementary data are available at Bioinformatics online. © The Author(s) 2017. Published by Oxford University Press.

Who gets a lung transplant? Assessing the psychosocial decision-making process for transplant listing

PubMed Central

Skillings, Jared Lyon

In the United States, there is a significant shortage of available donor organs. This requires transplant professionals to hold simultaneous, yet divergent roles as (1) advocates for patients who are in need of a lifesaving transplant, and (2) responsible stewards in the allocation of scarce donor organs. In order to balance these roles, most transplant teams utilize a committee based decision-making process to select suitable candidates for the transplant waiting list. These committees use medical and psychosocial criteria to guide their decision to list a patient. Transplant regulatory bodies have established medical standards for identifying appropriate medical candidates for transplantation. However, transplant regulatory bodies have not developed policies to standardize psychosocial criteria for listing patients. This affords transplant centers the autonomy to develop their own psychosocial criteria for determining which patients will be placed on the transplant waiting list. This lack of a standardized policy has resulted in inconsistent psychosocial practices amongst transplant centers nationwide. Since there has been no formal review of the inconsistency in psychosocial policy and practice, this paper seeks to explore the non-standardized psychosocial approach to organ transplant listing. The authors review factors that are relevant to the standardization of the psychosocial decision-making process, including shared decision-making, clinician judgment, bias in decision-making and moral distress in transplant staff. We conclude with a discussion about the impact of these issues on psychosocial practices in solid organ transplantation. PMID:29043272

Interagency Oncology Task Force Fellowship

Cancer.gov

In collaboration with FDA, these fellowships train scientists in research and research-related regulatory review, policies, and regulations to develop a skill set that bridges the two disparate processes.

Regulatory requirements for clinical trial and marketing authorisation application for cell-based medicinal products.

PubMed

Salmikangas, P; Flory, E; Reinhardt, J; Hinz, T; Maciulaitis, R

2010-01-01

The new era of regenerative medicine has led to rapid development of new innovative therapies especially for diseases and tissue/organ defects for which traditional therapies and medicinal products have not provided satisfactory outcome. Although the clinical use and developments of cell-based medicinal products (CBMPs) could be witnessed already for a decade, robust scientific and regulatory provisions for these products have only recently been enacted. The new Regulation for Advanced Therapies (EC) 1394/2007 together with the revised Annex I, Part IV of Directive 2001/83/EC provides the new legal framework for CBMPs. The wide variety of cell-based products and the foreseen limitations (small sample sizes, short shelf life) vs. particular risks (microbiological purity, variability, immunogenicity, tumourigenicity) associated with CBMPs have called for a flexible, case-by-case regulatory approach for these products. Consequently, a risk-based approach has been developed to allow definition of the amount of scientific data needed for a Marketing Authorisation Application (MAA) of each CBMP. The article provides further insight into the initial risk evaluation, as well as to the quality, non-clinical, and clinical requirements of CBMPs. Special somatic cell therapies designed for active immunotherapy are also addressed.

Porcine Tissue-Specific Regulatory Networks Derived from Meta-Analysis of the Transcriptome

PubMed Central

Pérez-Montarelo, Dafne; Hudson, Nicholas J.; Fernández, Ana I.; Ramayo-Caldas, Yuliaxis; Dalrymple, Brian P.; Reverter, Antonio

2012-01-01

The processes that drive tissue identity and differentiation remain unclear for most tissue types. So are the gene networks and transcription factors (TF) responsible for the differential structure and function of each particular tissue, and this is particularly true for non model species with incomplete genomic resources. To better understand the regulation of genes responsible for tissue identity in pigs, we have inferred regulatory networks from a meta-analysis of 20 gene expression studies spanning 480 Porcine Affymetrix chips for 134 experimental conditions on 27 distinct tissues. We developed a mixed-model normalization approach with a covariance structure that accommodated the disparity in the origin of the individual studies, and obtained the normalized expression of 12,320 genes across the 27 tissues. Using this resource, we constructed a network, based on the co-expression patterns of 1,072 TF and 1,232 tissue specific genes. The resulting network is consistent with the known biology of tissue development. Within the network, genes clustered by tissue and tissues clustered by site of embryonic origin. These clusters were significantly enriched for genes annotated in key relevant biological processes and confirm gene functions and interactions from the literature. We implemented a Regulatory Impact Factor (RIF) metric to identify the key regulators in skeletal muscle and tissues from the central nervous systems. The normalization of the meta-analysis, the inference of the gene co-expression network and the RIF metric, operated synergistically towards a successful search for tissue-specific regulators. Novel among these findings are evidence suggesting a novel key role of ERCC3 as a muscle regulator. Together, our results recapitulate the known biology behind tissue specificity and provide new valuable insights in a less studied but valuable model species. PMID:23049964

In silico regenerative medicine: how computational tools allow regulatory and financial challenges to be addressed in a volatile market

PubMed Central

Geris, L.; Guyot, Y.; Schrooten, J.; Papantoniou, I.

2016-01-01

The cell therapy market is a highly volatile one, due to the use of disruptive technologies, the current economic situation and the small size of the market. In such a market, companies as well as academic research institutes are in need of tools to advance their understanding and, at the same time, reduce their R&D costs, increase product quality and productivity, and reduce the time to market. An additional difficulty is the regulatory path that needs to be followed, which is challenging in the case of cell-based therapeutic products and should rely on the implementation of quality by design (QbD) principles. In silico modelling is a tool that allows the above-mentioned challenges to be addressed in the field of regenerative medicine. This review discusses such in silico models and focuses more specifically on the bioprocess. Three (clusters of) examples related to this subject are discussed. The first example comes from the pharmaceutical engineering field where QbD principles and their implementation through the use of in silico models are both a regulatory and economic necessity. The second example is related to the production of red blood cells. The described in silico model is mainly used to investigate the manufacturing process of the cell-therapeutic product, and pays special attention to the economic viability of the process. Finally, we describe the set-up of a model capturing essential events in the development of a tissue-engineered combination product in the context of bone tissue engineering. For each of the examples, a short introduction to some economic aspects is given, followed by a description of the in silico tool or tools that have been developed to allow the implementation of QbD principles and optimal design. PMID:27051516

In silico regenerative medicine: how computational tools allow regulatory and financial challenges to be addressed in a volatile market.

PubMed

Geris, L; Guyot, Y; Schrooten, J; Papantoniou, I

2016-04-06

The cell therapy market is a highly volatile one, due to the use of disruptive technologies, the current economic situation and the small size of the market. In such a market, companies as well as academic research institutes are in need of tools to advance their understanding and, at the same time, reduce their R&D costs, increase product quality and productivity, and reduce the time to market. An additional difficulty is the regulatory path that needs to be followed, which is challenging in the case of cell-based therapeutic products and should rely on the implementation of quality by design (QbD) principles. In silico modelling is a tool that allows the above-mentioned challenges to be addressed in the field of regenerative medicine. This review discusses such in silico models and focuses more specifically on the bioprocess. Three (clusters of) examples related to this subject are discussed. The first example comes from the pharmaceutical engineering field where QbD principles and their implementation through the use of in silico models are both a regulatory and economic necessity. The second example is related to the production of red blood cells. The described in silico model is mainly used to investigate the manufacturing process of the cell-therapeutic product, and pays special attention to the economic viability of the process. Finally, we describe the set-up of a model capturing essential events in the development of a tissue-engineered combination product in the context of bone tissue engineering. For each of the examples, a short introduction to some economic aspects is given, followed by a description of the in silico tool or tools that have been developed to allow the implementation of QbD principles and optimal design.

It’s OK to Fail: Individual and Dyadic Regulatory Antecedents of Mastery Motivation in Preschool

PubMed Central

Lunkenheimer, Erika; Wang, Jun

2017-01-01

Mastery motivation is closely related to children’s regulatory processes and is socialized by parents. However, we know little about how individual child and dyadic parent-child regulatory processes work together to foster the early development of mastery motivation in preschool. The present study examined dyadic persistence in parent-child interactions, children’s effortful control, and children’s successful versus failed attempts in a challenging object mastery task at age 3.5 years and their prediction of teacher ratings of object-oriented and social mastery motivation in preschool at a 4-month follow-up (N = 100). Path analytic models revealed that greater dyadic persistence during parent-child interactions predicted children’s higher levels of social mastery. A greater rate of both successful and failed attempts at a challenging task predicted children’s higher levels of object mastery. However, failed attempts were positively related to concurrent individual and dyadic regulatory measures, whereas successful attempts were not. Findings suggest that parent-child coregulation makes a significant contribution to mastery motivation development and that there may be distinct antecedents for object-oriented versus social forms of mastery motivation. Findings also suggest that a child’s early ability to persist in the face of failure may be an important predictor of mastery motivation in preschool. PMID:28966542

It's OK to Fail: Individual and Dyadic Regulatory Antecedents of Mastery Motivation in Preschool.

PubMed

Lunkenheimer, Erika; Wang, Jun

2017-05-01

Mastery motivation is closely related to children's regulatory processes and is socialized by parents. However, we know little about how individual child and dyadic parent-child regulatory processes work together to foster the early development of mastery motivation in preschool. The present study examined dyadic persistence in parent-child interactions, children's effortful control, and children's successful versus failed attempts in a challenging object mastery task at age 3.5 years and their prediction of teacher ratings of object-oriented and social mastery motivation in preschool at a 4-month follow-up ( N = 100). Path analytic models revealed that greater dyadic persistence during parent-child interactions predicted children's higher levels of social mastery. A greater rate of both successful and failed attempts at a challenging task predicted children's higher levels of object mastery. However, failed attempts were positively related to concurrent individual and dyadic regulatory measures, whereas successful attempts were not. Findings suggest that parent-child coregulation makes a significant contribution to mastery motivation development and that there may be distinct antecedents for object-oriented versus social forms of mastery motivation. Findings also suggest that a child's early ability to persist in the face of failure may be an important predictor of mastery motivation in preschool.

Reconstructing the regulatory circuit of cell fate determination in yeast mating response.

PubMed

Shao, Bin; Yuan, Haiyu; Zhang, Rongfei; Wang, Xuan; Zhang, Shuwen; Ouyang, Qi; Hao, Nan; Luo, Chunxiong

2017-07-01

Massive technological advances enabled high-throughput measurements of proteomic changes in biological processes. However, retrieving biological insights from large-scale protein dynamics data remains a challenging task. Here we used the mating differentiation in yeast Saccharomyces cerevisiae as a model and developed integrated experimental and computational approaches to analyze the proteomic dynamics during the process of cell fate determination. When exposed to a high dose of mating pheromone, the yeast cell undergoes growth arrest and forms a shmoo-like morphology; however, at intermediate doses, chemotropic elongated growth is initialized. To understand the gene regulatory networks that control this differentiation switch, we employed a high-throughput microfluidic imaging system that allows real-time and simultaneous measurements of cell growth and protein expression. Using kinetic modeling of protein dynamics, we classified the stimulus-dependent changes in protein abundance into two sources: global changes due to physiological alterations and gene-specific changes. A quantitative framework was proposed to decouple gene-specific regulatory modes from the growth-dependent global modulation of protein abundance. Based on the temporal patterns of gene-specific regulation, we established the network architectures underlying distinct cell fates using a reverse engineering method and uncovered the dose-dependent rewiring of gene regulatory network during mating differentiation. Furthermore, our results suggested a potential crosstalk between the pheromone response pathway and the target of rapamycin (TOR)-regulated ribosomal biogenesis pathway, which might underlie a cell differentiation switch in yeast mating response. In summary, our modeling approach addresses the distinct impacts of the global and gene-specific regulation on the control of protein dynamics and provides new insights into the mechanisms of cell fate determination. We anticipate that our integrated experimental and modeling strategies could be widely applicable to other biological systems.

The simcyp population based simulator: architecture, implementation, and quality assurance.

PubMed

Jamei, Masoud; Marciniak, Steve; Edwards, Duncan; Wragg, Kris; Feng, Kairui; Barnett, Adrian; Rostami-Hodjegan, Amin

2013-01-01

Developing a user-friendly platform that can handle a vast number of complex physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models both for conventional small molecules and larger biologic drugs is a substantial challenge. Over the last decade the Simcyp Population Based Simulator has gained popularity in major pharmaceutical companies (70% of top 40 - in term of R&D spending). Under the Simcyp Consortium guidance, it has evolved from a simple drug-drug interaction tool to a sophisticated and comprehensive Model Based Drug Development (MBDD) platform that covers a broad range of applications spanning from early drug discovery to late drug development. This article provides an update on the latest architectural and implementation developments within the Simulator. Interconnection between peripheral modules, the dynamic model building process and compound and population data handling are all described. The Simcyp Data Management (SDM) system, which contains the system and drug databases, can help with implementing quality standards by seamless integration and tracking of any changes. This also helps with internal approval procedures, validation and auto-testing of the new implemented models and algorithms, an area of high interest to regulatory bodies.

Key design considerations on comparative clinical efficacy studies for biosimilars: adalimumab as an example.

PubMed

Lai, Zhihong; La Noce, Anna

2016-01-01

The global development of a biosimilar product is a methodologically complex affair, lined with potential design pitfalls and operational missteps to be avoided. Without careful attention to experimental design and meticulous execution, a development programme may fail to demonstrate equivalence, as would be anticipated for a biosimilar product, and not receive regulatory approval based on current guidance. In order to demonstrate similarity of a biosimilar product versus the originator (ie, the branded product), based on regulatory guidance, a stepwise approach is usually taken, starting with a comprehensive structural and functional characterisation of the new biological moiety. Given the sequential nature of the review process, the extent and nature of the non-clinical in vivo studies and the clinical studies to be performed depend on the level of evidence obtained in these previous step(s). A clinical efficacy trial is often required to further demonstrate biosimilarity of the two products (biosimilar vs branded) in terms of comparative safety and effectiveness. Owing to the focus on demonstrating biosimilarity and not safety and efficacy de novo, designing an adequate phase III (potentially pivotal) clinical efficacy study of a biosimilar may present some unique challenges. Using adalimumab as an example, we highlight design elements that may deserve special attention.

Simulated maximum likelihood method for estimating kinetic rates in gene expression.

PubMed

Tian, Tianhai; Xu, Songlin; Gao, Junbin; Burrage, Kevin

2007-01-01

Kinetic rate in gene expression is a key measurement of the stability of gene products and gives important information for the reconstruction of genetic regulatory networks. Recent developments in experimental technologies have made it possible to measure the numbers of transcripts and protein molecules in single cells. Although estimation methods based on deterministic models have been proposed aimed at evaluating kinetic rates from experimental observations, these methods cannot tackle noise in gene expression that may arise from discrete processes of gene expression, small numbers of mRNA transcript, fluctuations in the activity of transcriptional factors and variability in the experimental environment. In this paper, we develop effective methods for estimating kinetic rates in genetic regulatory networks. The simulated maximum likelihood method is used to evaluate parameters in stochastic models described by either stochastic differential equations or discrete biochemical reactions. Different types of non-parametric density functions are used to measure the transitional probability of experimental observations. For stochastic models described by biochemical reactions, we propose to use the simulated frequency distribution to evaluate the transitional density based on the discrete nature of stochastic simulations. The genetic optimization algorithm is used as an efficient tool to search for optimal reaction rates. Numerical results indicate that the proposed methods can give robust estimations of kinetic rates with good accuracy.

British Columbia's fish health regulatory framework's contribution to sustainability goals related to salmon aquaculture.

PubMed

Stephen, Craig; Dicicco, Emiliano; Munk, Brandon

2008-12-01

Salmon farming is a significant contribution to the global seafood market to which the goal of sustainability is often applied. Diseases related to farms are perhaps the most contentious issues associated with sustainable salmon farming. We reviewed literature and policies in British Columbia, Canada, as well as interviewed key informants to examine how fish health regulations do or could support sustainability goals. We found four main obstacles to the development and application of a sustainability-based health management system. First, salmon farming faced the same challenges as other industries when trying to establish an operational definition of sustainability that captures all stakeholders' interests. Second, there was no program responsible for integrating the various regulations, responsible departments, and monitoring efforts to develop a comprehensive view of sustainability. Third, there was inadequate research base and social consensus on the criteria that should be used to track health outcomes for sustainability purposes. Fourth, the regulatory and management paradigm for salmon farming has been focused on diseases and pathogens as opposed to embracing a more inclusive health promotion model that includes biotic, abiotic, and social determinants of health. A transparent and inclusive participatory process that effectively links expert views with community and industry concerns should serve as the foundation for the next generation of health management regulations for salmon farming.

US Food and Drug Administration Perspectives on Clinical Mass Spectrometry.

PubMed

Lathrop, Julia Tait; Jeffery, Douglas A; Shea, Yvonne R; Scholl, Peter F; Chan, Maria M

2016-01-01

Mass spectrometry-based in vitro diagnostic devices that measure proteins and peptides are underutilized in clinical practice, and none has been cleared or approved by the Food and Drug Administration (FDA) for marketing or for use in clinical trials. One way to increase their utilization is through enhanced interactions between the FDA and the clinical mass spectrometry community to improve the validation and regulatory review of these devices. As a reference point from which to develop these interactions, this article surveys the FDA's regulation of mass spectrometry-based devices, explains how the FDA uses guidance documents and standards in the review process, and describes the FDA's previous outreach to stakeholders. Here we also discuss how further communication and collaboration with the clinical mass spectrometry communities can identify opportunities for the FDA to provide help in the development of mass spectrometry-based devices and enhance their entry into the clinic. © 2015 American Association for Clinical Chemistry.

Potency assays for therapeutic live whole cell cancer vaccines.

PubMed

Petricciani, John; Egan, William; Vicari, Giuseppe; Furesz, John; Schild, Geoffrey

2007-04-01

Therapeutic cancer vaccines are under development with the goal of enhancing the body's immune response to cancer cells sufficient to arrest cancer cell growth. Among the various approaches being used are those based on whole tumor cells. Developing a suitable measure of the potency of such vaccines presents a significant challenge because neither cellular associated markers nor in vivo biological responses that are correlated with efficacy have been identified; nevertheless, manufacturers and regulatory agencies will need to develop methods to evaluate these products. At this moment, the challenge for manufacturers who are developing whole cell vaccines is to demonstrate batch-to-batch consistency for the vaccine used in clinical studies and to show that comparable vaccine batches have the same capacity to achieve an acceptable level of biological activity that may be related to efficacy. This is particularly challenging in that animal models to test that activity do not exist and direct serological or immunological correlates of clinical protection are not available because protection has not yet been established in clinical trials. In the absence of well-defined biological markers and tests for manufacturing consistency, manufacturers and regulators will need to rely heavily on a highly reproducible manufacturing process--the consistency of the process therefore becomes critical. In developing regulatory approaches to whole cell cancer vaccines, the experience from the field of infectious disease vaccines should be examined for general guidance. A framework that draws heavily on the field of infectious disease vaccines is presented and suggests that at this point in the development of this new class of products, it is reasonable to develop data on quantitative antigen expression as a measure of potency with the expectation that when clinical efficacy has been established it will confirm the appropriateness of this approach. But because this will not be known until the end of a pivotal trial, a bioassay should be considered and run in parallel. Several examples of bioassays are presented along with their advantages and disadvantages. The final selection of a potency assay for use in lot release of a commercializable therapeutic whole cell vaccine ultimately will depend on the totality of the data available at the time of approval by regulatory agencies. Based on information currently available, it is likely that quantitative antigen expression or a bioassay could be used to measure potency. If both are determined to be acceptable, the use of quantitative antigen expression could be considered for routine lot release, while the bioassay could be reserved for use as one of the elements in establishing comparability when manufacturing changes are being considered after approval.

A Review of Information for Managing Aging in Nuclear Power Plants

DOE Office of Scientific and Technical Information (OSTI.GOV)

WC Morgan; JV Livingston

1995-09-01

Age related degradation effects in safety related systems of nuclear power plants should be managed to prevent safety margins from eroding below the acceptable limits provided in plant design bases. The Nuclear Plant Aging Research (NPAR) Pro- gram, conducted under the auspices of the U.S. Nuclear Regulatory Commission (NRC), Office of Nuclear Regulatory Research, and other related aging management programs are developing technical information on managing aging. The aging management process central to these efforts consists of three key elements: 1) selecting structures, systems, and components (SSCs) in which aging should be controlled; 2) understanding the mechanisms and rates ofmore » degradation in these SSCs; and 3) managing degradation through effective inspection, surveillance, condition monitoring, trending, record keeping, mainten- ance, refurbishment, replacement, and adjustments in the operating environment and service conditions. This document concisely reviews and integrates information developed under the NPAR Program and other aging management studies and other available information related to understanding and managing age-related degradation effects and provides specific refer- ences to more comprehensive information on the same subjects.« less

Food irradiation: regulatory aspects in the Asia and Pacific region

NASA Astrophysics Data System (ADS)

Luckman, Gary James

2002-03-01

Irradiation treatment of food is becoming an increasingly accepted processing option for countries in the Asia Pacific region wishing to meet growing sanitary and phytosanitary requirements in international trade. There remain however, large differences between the regulatory requirements in the countries in this region. This paper gives an outline on existing food irradiation regulations in the separate countries of the Asia Pacific region. New developments such as the recent decision by the Australia New Zealand Food Authority to start assessing applications for food irradiation treatment are discussed. Australia's intention to regulate the export of food treated by irradiation will also be outlined. Details of the decision to harmonise food irradiation regulations by 13 countries in the Asia Pacific region based on conformance with Codex requirements is outlined. The likelihood of other Asia Pacific countries enacting similar harmonisation of their regulations will be examined. Future development such as certification of irradiation as a sanitary treatment for food are discussed. The expected result of these initiatives is a likely increase in irradiated foods traded within the Asia Pacific region.

Regulating and Litigating in the Public Interest

PubMed Central

Hawkes, Corinna

2007-01-01

The pressure to regulate the marketing of high-energy, nutrient-poor foods to young people has been mounting in light of concern about rising worldwide levels of overweight and obesity. In 2004, the World Health Organization called on governments, industry, and civil society to act to reduce unhealthy marketing messages. Since then, important changes have taken place in the global regulatory environment regarding the marketing of food to young people. Industry has developed self-regulatory approaches, civil society has campaigned for statutory restrictions, and governments have dealt with a range of regulatory proposals. Still, there have been few new regulations that restrict food marketing to young people. Despite calls for evidence-based policy, new regulatory developments appear to have been driven less by evidence than by ethics. PMID:17901436

QSAR modeling for predicting mutagenic toxicity of diverse chemicals for regulatory purposes.

PubMed

Basant, Nikita; Gupta, Shikha

2017-06-01

The safety assessment process of chemicals requires information on their mutagenic potential. The experimental determination of mutagenicity of a large number of chemicals is tedious and time and cost intensive, thus compelling for alternative methods. We have established local and global QSAR models for discriminating low and high mutagenic compounds and predicting their mutagenic activity in a quantitative manner in Salmonella typhimurium (TA) bacterial strains (TA98 and TA100). The decision treeboost (DTB)-based classification QSAR models discriminated among two categories with accuracies of >96% and the regression QSAR models precisely predicted the mutagenic activity of diverse chemicals yielding high correlations (R 2 ) between the experimental and model-predicted values in the respective training (>0.96) and test (>0.94) sets. The test set root mean squared error (RMSE) and mean absolute error (MAE) values emphasized the usefulness of the developed models for predicting new compounds. Relevant structural features of diverse chemicals that were responsible and influence the mutagenic activity were identified. The applicability domains of the developed models were defined. The developed models can be used as tools for screening new chemicals for their mutagenicity assessment for regulatory purpose.

Regulatory and information support for evaluation of biological productivity of Ukrainian forests and climate change

NASA Astrophysics Data System (ADS)

Lakyda, Petro; Vasylyshyn, Roman; Lakyda, Ivan

2013-04-01

Stabilization and preservation of the planet's climate system today is regarded as one of the most important global political-economic, environmental and social problems of mankind. Rising concentration of carbon dioxide in the planet's atmosphere due to anthropogenic impact is the main reason leading to global climate change. Due to the above mentioned, social demands on forests are changing their biosphere role and function of natural sink of greenhouse gases becomes top priority. It is known that one of the most essential components of biological productivity of forests is their live biomass. Absorption, long-term sequestration of carbon and generation of oxygen are secured by its components. System research of its parametric structure and development of regulatory and reference information for assessment of aboveground live biomass components of trees and stands of the main forest-forming tree species in Ukraine began over twenty-five years ago at the department of forest mensuration and forest inventory of National University of Life and Environmental Sciences of Ukraine, involving staff from other research institutions. Today, regulatory and reference materials for evaluation of parametric structure of live biomass are developed for trees of the following major forest-forming tree species of Ukraine: Scots pine of natural and artificial origin, Crimean pine, Norway spruce, silver fir, pedunculate oak, European beech, hornbeam, ash, common birch, aspen and black alder (P.I. Lakyda et al., 2011). An ongoing process on development of similar regulatory and reference materials for forest stands of the abovementioned forest-forming tree species of Ukraine is secured by scientists of departments of forest management, and forest mensuration and forest inventory. The total experimental research base is 609 temporary sample plots, where 4880 model trees were processed, including 3195 model trees with estimates of live biomass components. Laboratory studies conducted on 1743 research sections of tree stems, 809 samples of crown branches, 2560 model tree greenery branches, 346 batches of needles and 534 batches of leaves. These materials have high scientific and practical value, forming a basis for quantitative evaluation of biological productivity of forests in Ukraine, which are of great importance for mitigation of climate change. They also can be used as a data source for development of systems of models of various purposes, which find their application in Ukrainian and world forest science and practice.

Evidence-based causation in toxicology: A 10-year retrospective.

PubMed

James, R C; Britt, J K; Halmes, N C; Guzelian, P S

2015-12-01

We introduced Evidence-based Toxicology (EBT) in 2005 to address the disparities that exist between the various Weight-of-Evidence (WOE) methods typically applied in the regulatory hazard decision-making arena and urged toxicologists to adopt the evidence-based guidelines long-utilized in medicine (i.e., Evidence-Based Medicine or EBM). This review of the activities leading to the adoption of evidence-based methods and EBT during the last decade demonstrates how fundamental concepts that form EBT, such as the use of systematic reviews to capture and consider all available information, are improving toxicological evaluations performed by various groups and agencies. We reiterate how the EBT framework, a process that provides a method for performing human chemical causation analyses in an objective, transparent and reproducible manner, differs significantly from past and current regulatory WOE approaches. We also discuss why the uncertainties associated with regulatory WOE schemes lead to a definition of the term "risk" that contains unquantifiable uncertainties not present in this term as it is used in epidemiology and medicine. We believe this distinctly different meaning of "risk" should be clearly conveyed to those not familiar with this difference (e.g., the lay public), when theoretical/nomologic risks associated with chemical-induced toxicities are presented outside of regulatory and related scientific parlance. © The Author(s) 2015.

Building Synergy between Regulatory and HTA Agencies beyond Processes and Procedures-Can We Effectively Align the Evidentiary Requirements? A Survey of Stakeholder Perceptions.

PubMed

Wang, Ting; McAuslane, Neil; Liberti, Lawrence; Leufkens, Hubert; Hövels, Anke

2018-06-01

To evaluate the current practice of companies and agencies to assess the changes made in aligning regulatory and health technology assessment (HTA) stakeholders; to identify areas of commonality of evidentiary requirements that could occur; and to identify strategic issues and trends of regulatory and HTA synergy. Two separate questionnaires were developed to assess stakeholders' perceptions on regulatory and HTA alignment, one for pharmaceutical companies and the other for regulatory and HTA agencies. The responses were analyzed using descriptive statistics. Seven regulatory and 8 HTA agencies from Australia, Canada, and Europe and 19 international companies developing innovative medicine responded to the survey. This study provided a snapshot of the current regulatory and HTA landscape. Changes made over the past 5 years were reflected in three main areas: there is an increasing interaction between regulatory and HTA agencies; current conditional regulatory approvals are not always linked with flexible HTA approaches; and companies are more supportive of joint scientific advice. Four types of evidentiary requirements were identified as building blocks for better alignment: acceptable primary end points, inclusion of an active comparator, use of patient-reported outcomes, and choice and use of surrogate end point. The study showed that the gap between regulatory and HTA requirements has narrowed over the past 5 years. All respondents supported synergy between regulatory and HTA stakeholders, and the study provided several recommendations on how to further improve evidentiary alignment including the provision of joint scientific advice, which was rated as a key strategy by both agencies and companies. Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Automatic reconstruction of a bacterial regulatory network using Natural Language Processing

PubMed Central

Rodríguez-Penagos, Carlos; Salgado, Heladia; Martínez-Flores, Irma; Collado-Vides, Julio

2007-01-01

Background Manual curation of biological databases, an expensive and labor-intensive process, is essential for high quality integrated data. In this paper we report the implementation of a state-of-the-art Natural Language Processing system that creates computer-readable networks of regulatory interactions directly from different collections of abstracts and full-text papers. Our major aim is to understand how automatic annotation using Text-Mining techniques can complement manual curation of biological databases. We implemented a rule-based system to generate networks from different sets of documents dealing with regulation in Escherichia coli K-12. Results Performance evaluation is based on the most comprehensive transcriptional regulation database for any organism, the manually-curated RegulonDB, 45% of which we were able to recreate automatically. From our automated analysis we were also able to find some new interactions from papers not already curated, or that were missed in the manual filtering and review of the literature. We also put forward a novel Regulatory Interaction Markup Language better suited than SBML for simultaneously representing data of interest for biologists and text miners. Conclusion Manual curation of the output of automatic processing of text is a good way to complement a more detailed review of the literature, either for validating the results of what has been already annotated, or for discovering facts and information that might have been overlooked at the triage or curation stages. PMID:17683642

Regulatory elements driving the expression of skeletal lineage reporters differ during bone development and adulthood.

PubMed

Stiers, Pieter-Jan; van Gastel, Nick; Moermans, Karen; Stockmans, Ingrid; Carmeliet, Geert

2017-12-01

To improve bone healing or regeneration more insight in the fate and role of the different skeletal cell types is required. Mouse models for fate mapping and lineage tracing of skeletal cells, using stage-specific promoters, have advanced our understanding of bone development, a process that is largely recapitulated during bone repair. However, validation of these models is often only performed during development, whereas proof of the activity and specificity of the used promoters during the bone regenerative process is limited. Here, we show that the regulatory elements of the 6kb collagen type II promoter are not adequate to drive gene expression during bone repair. Similarly, the 2.3kb promoter of collagen type I lacks activity in adult mice, but the 3.2kb promoter is suitable. Furthermore, Cre-mediated fate mapping allows the visualization of progeny, but this label retention may hinder to distinguish these cells from ones with active expression of the marker at later time points. Together, our results show that the lineage-specific regulatory elements driving gene expression during bone development differ from those required later in life and during bone repair, and justify validation of lineage-specific cell tracing and gene silencing strategies during fracture healing and bone regenerative applications. Copyright © 2017 Elsevier Inc. All rights reserved.

Integrated Module and Gene-Specific Regulatory Inference Implicates Upstream Signaling Networks

PubMed Central

Roy, Sushmita; Lagree, Stephen; Hou, Zhonggang; Thomson, James A.; Stewart, Ron; Gasch, Audrey P.

2013-01-01

Regulatory networks that control gene expression are important in diverse biological contexts including stress response and development. Each gene's regulatory program is determined by module-level regulation (e.g. co-regulation via the same signaling system), as well as gene-specific determinants that can fine-tune expression. We present a novel approach, Modular regulatory network learning with per gene information (MERLIN), that infers regulatory programs for individual genes while probabilistically constraining these programs to reveal module-level organization of regulatory networks. Using edge-, regulator- and module-based comparisons of simulated networks of known ground truth, we find MERLIN reconstructs regulatory programs of individual genes as well or better than existing approaches of network reconstruction, while additionally identifying modular organization of the regulatory networks. We use MERLIN to dissect global transcriptional behavior in two biological contexts: yeast stress response and human embryonic stem cell differentiation. Regulatory modules inferred by MERLIN capture co-regulatory relationships between signaling proteins and downstream transcription factors thereby revealing the upstream signaling systems controlling transcriptional responses. The inferred networks are enriched for regulators with genetic or physical interactions, supporting the inference, and identify modules of functionally related genes bound by the same transcriptional regulators. Our method combines the strengths of per-gene and per-module methods to reveal new insights into transcriptional regulation in stress and development. PMID:24146602

Next generation and biosimilar monoclonal antibodies

PubMed Central

2011-01-01

The Next Generation and Biosimilar Monoclonal Antibodies: Essential Considerations Towards Regulatory Acceptance in Europe workshop, organized by the European Centre of Regulatory Affairs Freiburg (EUCRAF), was held February 3–4, 2011 in Freiburg, Germany. The workshop attracted over 100 attendees from 15 countries, including regulators from 11 agencies, who interacted over the course of two days. The speakers presented their authoritative views on monoclonal antibodies (mAbs) as attractive targets for development, the experience to date with the regulatory process for biosimilar medicinal products, the European Medicines Agency draft guideline on biosimilar mAbs, as well as key elements in the development of mAbs. Participants engaged in many lively discussions, and much speculation on the nature of the quality, non-clinical and clinical requirements for authorization of biosimilar mAbs. PMID:21487235

Altered Immune Regulation in Type 1 Diabetes

PubMed Central

Zóka, András; Műzes, Györgyi; Somogyi, Anikó; Varga, Tímea; Szémán, Barbara; Al-Aissa, Zahra; Hadarits, Orsolya; Firneisz, Gábor

2013-01-01

Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic β-cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development. PMID:24285974

Nuclear Regulatory Commission activities to prepare for reviewing license applications and issuing licenses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Uleck, R.B.; DeFino, C.V.

1991-12-31

The Low-Level Radioactive Waste Policy Amendments Act of 1985 (LLRWPAA) assigned States the responsibility to provide for disposal of commercial low-level radioactive waste (LLRW) by 1993. The LLRWPAA also required the US Nuclear Regulatory Commission (NRC) to establish procedures and develop the technical review capability to process license applications for new LLRW disposal facilities. Under the LLRWPAA, NRC is required, to the extent practicable, to complete its review of an LLRW disposal facility license application within 15 months of its submittal by a State. This provision of the LLRWPAA helps ensure that NRC, in addition to protecting public health andmore » safety and the environment, facilitates States` achievement of LLRWPAA milestones for new facility development. A timely NRC review is needed for States to accomplish their objective of having new disposal facilities in operation on the dates prescribed in the LLRWPAA. To help assure NRC and States` compliance with the provisions of the LLRWPAA, NRC has developed a licensing review strategy that includes: (1) the further development of regulatory guidance, (2) enhancement of licensing review capability, and (3) prelicensing regulatory consultation with potential applicants.« less

Assessing new developments in the pre-market regulatory process of medical devices in the People's Republic of China.

PubMed

Zhang, Shixuan; Kriza, Christine; Kolominsky-Rabas, Peter L

2014-09-01

The objective of this paper is to provide a systematic overview of the Chinese medical device registration processes, identify challenges and suggest how these can be addressed. In addition, the paper will outline the impact of new policies and regulations since the restructuring of the China FDA. A systematic review was performed for journal articles between the year of 2009 and 2013 in the following databases: PubMed, ScienceDirect and Zhongguozhiwang. The review has identified 184 papers which were potentially relevant. Seventeen articles were included in the review, which highlights the challenges and opportunities related to the medical device registration process. In order to understand the actual impact of the regulation environment and its policies including the lack of regulatory guidance regular assessment updates are crucial. The results of this paper are aimed at informing regulatory bodies, health policy decision makers, national and international Health Technology Assessment networks as well as medical devices manufacturers.

Air Emissions Damages from Municipal Drinking Water Treatment Under Current and Proposed Regulatory Standards.

PubMed

Gingerich, Daniel B; Mauter, Meagan S

2017-09-19

Water treatment processes present intersectoral and cross-media risk trade-offs that are not presently considered in Safe Drinking Water Act regulatory analyses. This paper develops a method for assessing the air emission implications of common municipal water treatment processes used to comply with recently promulgated and proposed regulatory standards, including concentration limits for, lead and copper, disinfection byproducts, chromium(VI), strontium, and PFOA/PFOS. Life-cycle models of electricity and chemical consumption for individual drinking water unit processes are used to estimate embedded NO x , SO 2 , PM 2.5 , and CO 2 emissions on a cubic meter basis. We estimate air emission damages from currently installed treatment processes at U.S. drinking water facilities to be on the order of $500 million USD annually. Fully complying with six promulgated and proposed rules would increase baseline air emission damages by approximately 50%, with three-quarters of these damages originating from chemical manufacturing. Despite the magnitude of these air emission damages, the net benefit of currently implemented rules remains positive. For some proposed rules, however, the promise of net benefits remains contingent on technology choice.

Concepts and challenges in quantitative pharmacology and model-based drug development.

PubMed

Zhang, Liping; Pfister, Marc; Meibohm, Bernd

2008-12-01

Model-based drug development (MBDD) has been recognized as a concept to improve the efficiency of drug development. The acceptance of MBDD from regulatory agencies, industry, and academia has been growing, yet today's drug development practice is still distinctly distant from MBDD. This manuscript is aimed at clarifying the concept of MBDD and proposing practical approaches for implementing MBDD in the pharmaceutical industry. The following concepts are defined and distinguished: PK-PD modeling, exposure-response modeling, pharmacometrics, quantitative pharmacology, and MBDD. MBDD is viewed as a paradigm and a mindset in which models constitute the instruments and aims of drug development efforts. MBDD covers the whole spectrum of the drug development process instead of being limited to a certain type of modeling technique or application area. The implementation of MBDD requires pharmaceutical companies to foster innovation and make changes at three levels: (1) to establish mindsets that are willing to get acquainted with MBDD, (2) to align processes that are adaptive to the requirements of MBDD, and (3) to create a closely collaborating organization in which all members play a role in MBDD. Pharmaceutical companies that are able to embrace the changes MBDD poses will likely be able to improve their success rate in drug development, and the beneficiaries will ultimately be the patients in need.

Speeding Access to Vaccines and Medicines in Low- and Middle-Income Countries: A Case for Change and a Framework for Optimized Product Market Authorization

PubMed Central

Ahonkhai, Vincent; Portet, Alexandre; Hartman, Dan

2016-01-01

Background The United Nations Millennium Development Goals galvanized global efforts to alleviate suffering of the world’s poorest people through unprecedented public-private partnerships. Donor aid agencies have demonstrably saved millions of lives that might otherwise have been lost to disease through increased access to quality-assured vaccines and medicines. Yet, the introduction of these health interventions in low- and middle-income countries (LMICs) continues to face a time lag due to factors which remain poorly understood. Methods and Findings A recurring theme from our partnership engagements was that an optimized regulatory process would contribute to improved access to quality health products. Therefore, we investigated the current system for medicine and vaccine registration in LMICs as part of our comprehensive regulatory strategy. Here, we report a fact base of the registration timelines for vaccines and drugs used to treat certain communicable diseases in LMICs. We worked with a broad set of stakeholders, including the World Health Organization’s prequalification team, national regulatory authorities, manufacturers, procurers, and other experts, and collected data on the timelines between first submission and last approval of applications for product registration sub-Saharan Africa. We focused on countries with the highest burden of communicable disease and the greatest need for the products studied. The data showed a typical lag of 4 to 7 years between the first regulatory submission which was usually to a regulatory agency in a high-income country, and the final approval in Sub-Saharan Africa. Two of the three typical registration steps which products undergo before delivery in the countries involve lengthy timelines. Failure to leverage or rely on the findings from reviews already performed by competent regulatory authorities, disparate requirements for product approval by the countries, and lengthy timelines by manufacturers to respond to regulatory queries were key underlying factors for the delays. Conclusions We propose a series of measures which we developed in close collaboration with key stakeholders that could be taken to reduce registration time and to make safe, effective medicines more quickly available in countries where they are most needed. Many of these recommendations are being implemented by the responsible stakeholders, including the WHO prequalification team and the national regulatory authorities in Sub-Saharan Africa. Those efforts will be the focus of subsequent publications by the pertinent groups. PMID:27851831

Speeding Access to Vaccines and Medicines in Low- and Middle-Income Countries: A Case for Change and a Framework for Optimized Product Market Authorization.

PubMed

Ahonkhai, Vincent; Martins, Samuel F; Portet, Alexandre; Lumpkin, Murray; Hartman, Dan

2016-01-01

The United Nations Millennium Development Goals galvanized global efforts to alleviate suffering of the world's poorest people through unprecedented public-private partnerships. Donor aid agencies have demonstrably saved millions of lives that might otherwise have been lost to disease through increased access to quality-assured vaccines and medicines. Yet, the introduction of these health interventions in low- and middle-income countries (LMICs) continues to face a time lag due to factors which remain poorly understood. A recurring theme from our partnership engagements was that an optimized regulatory process would contribute to improved access to quality health products. Therefore, we investigated the current system for medicine and vaccine registration in LMICs as part of our comprehensive regulatory strategy. Here, we report a fact base of the registration timelines for vaccines and drugs used to treat certain communicable diseases in LMICs. We worked with a broad set of stakeholders, including the World Health Organization's prequalification team, national regulatory authorities, manufacturers, procurers, and other experts, and collected data on the timelines between first submission and last approval of applications for product registration sub-Saharan Africa. We focused on countries with the highest burden of communicable disease and the greatest need for the products studied. The data showed a typical lag of 4 to 7 years between the first regulatory submission which was usually to a regulatory agency in a high-income country, and the final approval in Sub-Saharan Africa. Two of the three typical registration steps which products undergo before delivery in the countries involve lengthy timelines. Failure to leverage or rely on the findings from reviews already performed by competent regulatory authorities, disparate requirements for product approval by the countries, and lengthy timelines by manufacturers to respond to regulatory queries were key underlying factors for the delays. We propose a series of measures which we developed in close collaboration with key stakeholders that could be taken to reduce registration time and to make safe, effective medicines more quickly available in countries where they are most needed. Many of these recommendations are being implemented by the responsible stakeholders, including the WHO prequalification team and the national regulatory authorities in Sub-Saharan Africa. Those efforts will be the focus of subsequent publications by the pertinent groups.

Innovations in vaccine development: can regulatory authorities keep up?

PubMed

Cox, Manon M J; Onraedt, Annelies

2012-10-01

Vaccine Production Summit San Francisco, CA, USA, 4-6 June 2012 IBC's 3rd Vaccine Production Summit featured 28 presentations discussing regulatory challenges in vaccine development, including the use of adjuvants, vaccine manufacturing and technology transfer, process development for vaccines and the role of quality by design, how to address vaccine stability, and how vaccine development timelines can be improved. The conference was run in parallel with the single-use applications for Biopharmaceutical Manufacturing conference. Approximately 250 attendees from large pharmaceutical companies, large and small biotech companies, vendors and a more limited number from academia were allowed to access sessions of either conference, including one shared session. This article summarizes the recurring themes across various presentations.

Genetic modification through oligonucleotide-mediated mutagenesis. A GMO regulatory challenge?

PubMed

Breyer, Didier; Herman, Philippe; Brandenburger, Annick; Gheysen, Godelieve; Remaut, Erik; Soumillion, Patrice; Van Doorsselaere, Jan; Custers, René; Pauwels, Katia; Sneyers, Myriam; Reheul, Dirk

2009-01-01

In the European Union, the definition of a GMO is technology-based. This means that a novel organism will be regulated under the GMO regulatory framework only if it has been developed with the use of defined techniques. This approach is now challenged with the emergence of new techniques. In this paper, we describe regulatory and safety issues associated with the use of oligonucleotide-mediated mutagenesis to develop novel organisms. We present scientific arguments for not having organisms developed through this technique fall within the scope of the EU regulation on GMOs. We conclude that any political decision on this issue should be taken on the basis of a broad reflection at EU level, while avoiding discrepancies at international level.

Structural responses to the obesity and non-communicable diseases epidemic: the Chilean Law of Food Labeling and Advertising.

PubMed

Corvalán, C; Reyes, M; Garmendia, M L; Uauy, R

2013-11-01

In 12 July 2012, the Chilean Senate approved the Law of Food Labeling and Advertising, resulting from the joint efforts of a group of health professionals, researchers and legislators who proposed a regulatory framework in support of healthy diets and active living. Its goal was to curb the ongoing epidemic increase of obesity and non-communicable diseases. Two actions included: (i) improving point of food purchase consumer information by incorporating easy-to-understand front-of-packages labeling and specific messages addressing critical nutrients, and (ii) decreasing children's exposure to unhealthy foods by restricting marketing, advertising and sales. We summarize the work related to the law's release and discuss the conclusions reached by the various expert committees that were convened by the Ministry of Health to guide the development of the regulatory norms. Throughout the process, the food industry has overtly expressed its disagreement with the regulatory effort. The final content of the regulatory norms is still pending; however there are suggestions that its implementation will be delayed and might be modified based on the industry lobbying actions. These lessons should contribute to show the need of anticipating and addressing potential barriers to obesity-prevention policy implementation, particularly with respect to the role of the private sector. © 2013 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of the International Association for the Study of Obesity.

The relationship between time perspective and self-regulatory processes, abilities and outcomes: a protocol for a meta-analytical review.

PubMed

Baird, Harriet M; Webb, Thomas L; Martin, Jilly; Sirois, Fuschia M

2017-07-05

Both theoretical and empirical evidence suggests that time perspective is likely to influence self-regulatory processes and outcomes. Despite the theoretical and practical significance of such relations, the relationship between time perspective and self-regulatory processes and outcomes across different measures, samples and life domains, including health, has yet to be explored. The proposed review will develop a taxonomy for classifying measures according to the self-regulatory process, ability or outcome that they are likely to reflect. Electronic scientific databases will be searched, along with relevant conference abstract booklets and citation lists. Additionally, a call for unpublished data will be submitted to relevant bodies. To be eligible for inclusion, studies must include a measure of time perspective and a measure of at least one self-regulatory process, ability and/ or outcome. Eligibility will not be restricted by publication date, language, type of sample or setting. The bivariate correlations will be extracted (or calculated) and submitted to a random-effects meta-analysis. The sample-weighted average effect size, heterogeneity, risk of bias and publication bias will be calculated, and the effects of categorical and continuous moderator variables on the effect sizes will be determined. The proposed meta-analysis will synthesise previously conducted research; thus, ethical approval is not required. The findings will be submitted for publication in an international peer-reviewed journal and reported as part of the first author’s PhD thesis. The findings will also be disseminated to the research community and, where appropriate, to other interested parties through presentations at relevant academic and non-academic conferences. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

The relationship between time perspective and self-regulatory processes, abilities and outcomes: a protocol for a meta-analytical review

PubMed Central

Baird, Harriet M; Webb, Thomas L; Martin, Jilly; Sirois, Fuschia M

2017-01-01

Introduction Both theoretical and empirical evidence suggests that time perspective is likely to influence self-regulatory processes and outcomes. Despite the theoretical and practical significance of such relations, the relationship between time perspective and self-regulatory processes and outcomes across different measures, samples and life domains, including health, has yet to be explored. Methods and analysis The proposed review will develop a taxonomy for classifying measures according to the self-regulatory process, ability or outcome that they are likely to reflect. Electronic scientific databases will be searched, along with relevant conference abstract booklets and citation lists. Additionally, a call for unpublished data will be submitted to relevant bodies. To be eligible for inclusion, studies must include a measure of time perspective and a measure of at least one self-regulatory process, ability and/ or outcome. Eligibility will not be restricted by publication date, language, type of sample or setting. The bivariate correlations will be extracted (or calculated) and submitted to a random-effects meta-analysis. The sample-weighted average effect size, heterogeneity, risk of bias and publication bias will be calculated, and the effects of categorical and continuous moderator variables on the effect sizes will be determined. Ethics and dissemination The proposed meta-analysis will synthesise previously conducted research; thus, ethical approval is not required. The findings will be submitted for publication in an international peer-reviewed journal and reported as part of the first author’s PhD thesis. The findings will also be disseminated to the research community and, where appropriate, to other interested parties through presentations at relevant academic and non-academic conferences. PMID:28679677

Toward a Safety Risk-Based Classification of Unmanned Aircraft

NASA Technical Reports Server (NTRS)

Torres-Pomales, Wilfredo

2016-01-01

There is a trend of growing interest and demand for greater access of unmanned aircraft (UA) to the National Airspace System (NAS) as the ongoing development of UA technology has created the potential for significant economic benefits. However, the lack of a comprehensive and efficient UA regulatory framework has constrained the number and kinds of UA operations that can be performed. This report presents initial results of a study aimed at defining a safety-risk-based UA classification as a plausible basis for a regulatory framework for UA operating in the NAS. Much of the study up to this point has been at a conceptual high level. The report includes a survey of contextual topics, analysis of safety risk considerations, and initial recommendations for a risk-based approach to safe UA operations in the NAS. The next phase of the study will develop and leverage deeper clarity and insight into practical engineering and regulatory considerations for ensuring that UA operations have an acceptable level of safety.

Overcoming regulatory and economic challenges facing pharmacogenomics.

PubMed

Cohen, Joshua P

2012-09-15

The number of personalized medicines and companion diagnostics in use in the United States has gradually increased over the past decade, from a handful of medicines and tests in 2001 to several dozen in 2011. However, the numbers have not reached the potential hoped for when the human genome project was completed in 2001. Significant clinical, regulatory, and economic barriers exist and persist. From a regulatory perspective, therapeutics and companion diagnostics are ideally developed simultaneously, with the clinical significance of the diagnostic established using data from the clinical development program of the corresponding therapeutic. Nevertheless, this is not (yet) happening. Most personalized medicines are personalized post hoc, that is, a companion diagnostic is developed separately and approved after the therapeutic. This is due in part to a separate and more complex regulatory process for diagnostics coupled with a lack of clear regulatory guidance. More importantly, payers have placed restrictions on reimbursement of personalized medicines and their companion diagnostics, given the lack of evidence on the clinical utility of many tests. To achieve increased clinical adoption of diagnostics and targeted therapies through more favorable reimbursement and incorporation in clinical practice guidelines, regulators will need to provide unambiguous guidance and manufacturers will need to bring more and better clinical evidence to the market place. Copyright © 2012 Elsevier B.V. All rights reserved.

Radiation processing: adapting to a changing world.

PubMed

Woolston, J

2009-01-01

The 15th International Meeting on Radiation Processing was held in London, UK, on 21-25 September 2008. It provided a forum for researchers, academics, the radiation processing industry and its users and regulators to review progress. This report focuses on the developments relevant to medical device sterilisation in products, processes, technology and the regulatory environment that were examined at the event.

A new roadmap for biopharmaceutical drug product development: Integrating development, validation, and quality by design.

PubMed

Martin-Moe, Sheryl; Lim, Fredric J; Wong, Rita L; Sreedhara, Alavattam; Sundaram, Jagannathan; Sane, Samir U

2011-08-01

Quality by design (QbD) is a science- and risk-based approach to drug product development. Although pharmaceutical companies have historically used many of the same principles during development, this knowledge was not always formally captured or proactively submitted to regulators. In recent years, the US Food and Drug Administration has also recognized the need for more controls in the drug manufacturing processes, especially for biological therapeutics, and it has recently launched an initiative for Pharmaceutical Quality for the 21st Century to modernize pharmaceutical manufacturing and improve product quality. In the biopharmaceutical world, the QbD efforts have been mainly focused on active pharmaceutical ingredient processes with little emphasis on drug product development. We present a systematic approach to biopharmaceutical drug product development using a monoclonal antibody as an example. The approach presented herein leverages scientific understanding of products and processes, risk assessments, and rational experimental design to deliver processes that are consistent with QbD philosophy without excessive incremental effort. Data generated using these approaches will not only strengthen data packages to support specifications and manufacturing ranges but hopefully simplify implementation of postapproval changes. We anticipate that this approach will positively impact cost for companies, regulatory agencies, and patients, alike. Copyright © 2011 Wiley-Liss, Inc.

Moving beyond 'rates, roads and rubbish': How do local governments make choices about healthy public policy to prevent obesity?

PubMed Central

Allender, Steven; Gleeson, Erin; Crammond, Brad; Sacks, Gary; Lawrence, Mark; Peeters, Anna; Loff, Bebe; Swinburn, Boyd

2009-01-01

While the causes of obesity are well known traditional education and treatment strategies do not appear to be making an impact. One solution as part of a broader complimentary set of strategies may be regulatory intervention at local government level to create environments for healthy nutrition and increased physical activity. Semi structured interviews were conducted with representatives of local government in Australia. Factors most likely to facilitate policy change were those supported by external funding, developed from an evidence base and sensitive to community and market forces. Barriers to change included a perceived or real lack of power to make change and the complexity of the legislative framework. The development of a systematic evidence base to provide clear feedback on the size and scope of the obesity epidemic at a local level, coupled with cost benefit analysis for any potential regulatory intervention, are crucial to developing a regulatory environment which creates the physical and social environment required to prevent obesity. PMID:19698170

[Dynamic hierarchy of regulatory peptides. Structure of the induction relations of regulators as the target for therapeutic agents].

PubMed

Koroleva, S V; Miasoedov, N F

2012-01-01

Based on the database information (literature period 1970-2010 gg.) on the effects of regulatory peptides (RP) and non-peptide neurotransmitters (dopamine, serotonin, norepi-nephrine, acetylcholine) it was analyzed of possible cascade processes of endogenous regulators. It was found that the entire continuum of RP and mediators is a chaotic soup of the ordered three-level compartments. Such a dynamic functional hierarchy of endogenous regulators allows to create start-up and corrective tasks for a variety of physiological functions. Some examples of static and dynamic patterns of induction processes of RP and mediators (that regulate the states of anxiety, depression, learning and memory, feeding behavior, reproductive processes, etc.) are considered.

Developmental plasticity and language: A comparative perspective

PubMed Central

Griebel, Ulrike; Pepperberg, Irene; Oller, D. Kimbrough

2016-01-01

The growing field of evo-devo is increasingly demonstrating the complexity of steps involved in genetic, intracellular regulatory, and extracellular environmental control of the development of phenotypes. A key result of such work is an account for the remarkable plasticity of organismal form in many species based on relatively minor changes in regulation of highly conserved genes and genetic processes. Accounting for behavioral plasticity is of similar potential interest but has received far less attention. Of particular interest is plasticity in communication systems, where human language represents an ultimate target for research. The present paper considers plasticity of language capabilities in a comparative framework, focusing attention on examples of a remarkable fact: Whereas there exist design features of mature human language that have never been observed to occur in nonhumans in the wild, many of these features can be developed to notable extents when nonhumans are enculturated through human training (especially with intensive social interaction). These examples of enculturated developmental plasticity across extremely diverse taxa suggest, consistent with the evo-devo theme of highly conserved processes in evolution, that human language is founded in part on cognitive capabilities that are indeed ancient and that even modern humans show self-organized emergence of many language capabilities in the context of rich enculturation, built on the special social/ecological history of the hominin line. Human culture can thus be seen as a regulatory system encouraging language development in the context of a cognitive background with many highly conserved features. PMID:27003391

Developmental Plasticity and Language: A Comparative Perspective.

PubMed

Griebel, Ulrike; Pepperberg, Irene M; Oller, D Kimbrough

2016-04-01

The growing field of evo-devo is increasingly demonstrating the complexity of steps involved in genetic, intracellular regulatory, and extracellular environmental control of the development of phenotypes. A key result of such work is an account for the remarkable plasticity of organismal form in many species based on relatively minor changes in regulation of highly conserved genes and genetic processes. Accounting for behavioral plasticity is of similar potential interest but has received far less attention. Of particular interest is plasticity in communication systems, where human language represents an ultimate target for research. The present paper considers plasticity of language capabilities in a comparative framework, focusing attention on examples of a remarkable fact: Whereas there exist design features of mature human language that have never been observed to occur in non-humans in the wild, many of these features can be developed to notable extents when non-humans are enculturated through human training (especially with intensive social interaction). These examples of enculturated developmental plasticity across extremely diverse taxa suggest, consistent with the evo-devo theme of highly conserved processes in evolution, that human language is founded in part on cognitive capabilities that are indeed ancient and that even modern humans show self-organized emergence of many language capabilities in the context of rich enculturation, built on the special social/ecological history of the hominin line. Human culture can thus be seen as a regulatory system encouraging language development in the context of a cognitive background with many highly conserved features. Copyright © 2016 Cognitive Science Society, Inc.

Reliability measurement during software development. [for a multisensor tracking system

NASA Technical Reports Server (NTRS)

Hecht, H.; Sturm, W. A.; Trattner, S.

1977-01-01

During the development of data base software for a multi-sensor tracking system, reliability was measured. The failure ratio and failure rate were found to be consistent measures. Trend lines were established from these measurements that provided good visualization of the progress on the job as a whole as well as on individual modules. Over one-half of the observed failures were due to factors associated with the individual run submission rather than with the code proper. Possible application of these findings for line management, project managers, functional management, and regulatory agencies is discussed. Steps for simplifying the measurement process and for use of these data in predicting operational software reliability are outlined.

Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper

PubMed Central

Lener, Thomas; Gimona, Mario; Aigner, Ludwig; Börger, Verena; Buzas, Edit; Camussi, Giovanni; Chaput, Nathalie; Chatterjee, Devasis; Court, Felipe A.; del Portillo, Hernando A.; O'Driscoll, Lorraine; Fais, Stefano; Falcon-Perez, Juan M.; Felderhoff-Mueser, Ursula; Fraile, Lorenzo; Gho, Yong Song; Görgens, André; Gupta, Ramesh C.; Hendrix, An; Hermann, Dirk M.; Hill, Andrew F.; Hochberg, Fred; Horn, Peter A.; de Kleijn, Dominique; Kordelas, Lambros; Kramer, Boris W.; Krämer-Albers, Eva-Maria; Laner-Plamberger, Sandra; Laitinen, Saara; Leonardi, Tommaso; Lorenowicz, Magdalena J.; Lim, Sai Kiang; Lötvall, Jan; Maguire, Casey A.; Marcilla, Antonio; Nazarenko, Irina; Ochiya, Takahiro; Patel, Tushar; Pedersen, Shona; Pocsfalvi, Gabriella; Pluchino, Stefano; Quesenberry, Peter; Reischl, Ilona G.; Rivera, Francisco J.; Sanzenbacher, Ralf; Schallmoser, Katharina; Slaper-Cortenbach, Ineke; Strunk, Dirk; Tonn, Torsten; Vader, Pieter; van Balkom, Bas W. M.; Wauben, Marca; Andaloussi, Samir El; Théry, Clotilde; Rohde, Eva; Giebel, Bernd

2015-01-01

Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed. PMID:26725829

Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper.

PubMed

Lener, Thomas; Gimona, Mario; Aigner, Ludwig; Börger, Verena; Buzas, Edit; Camussi, Giovanni; Chaput, Nathalie; Chatterjee, Devasis; Court, Felipe A; Del Portillo, Hernando A; O'Driscoll, Lorraine; Fais, Stefano; Falcon-Perez, Juan M; Felderhoff-Mueser, Ursula; Fraile, Lorenzo; Gho, Yong Song; Görgens, André; Gupta, Ramesh C; Hendrix, An; Hermann, Dirk M; Hill, Andrew F; Hochberg, Fred; Horn, Peter A; de Kleijn, Dominique; Kordelas, Lambros; Kramer, Boris W; Krämer-Albers, Eva-Maria; Laner-Plamberger, Sandra; Laitinen, Saara; Leonardi, Tommaso; Lorenowicz, Magdalena J; Lim, Sai Kiang; Lötvall, Jan; Maguire, Casey A; Marcilla, Antonio; Nazarenko, Irina; Ochiya, Takahiro; Patel, Tushar; Pedersen, Shona; Pocsfalvi, Gabriella; Pluchino, Stefano; Quesenberry, Peter; Reischl, Ilona G; Rivera, Francisco J; Sanzenbacher, Ralf; Schallmoser, Katharina; Slaper-Cortenbach, Ineke; Strunk, Dirk; Tonn, Torsten; Vader, Pieter; van Balkom, Bas W M; Wauben, Marca; Andaloussi, Samir El; Théry, Clotilde; Rohde, Eva; Giebel, Bernd

2015-01-01

Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.

76 FR 70195 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-10

... Change Relating to Amendments to the Order Audit Trail System Rules November 4, 2011. Pursuant to Section... members report to the Order Audit Trail System (``OATS'') information barriers put into place by the... the Commission, FINRA noted: Based on further development of the Order Audit System and determinations...

Expert Voices in Learning Improvisation: Shaping Regulation Processes through Experiential Influence

ERIC Educational Resources Information Center

de Bruin, Leon R.

2017-01-01

Interpersonal and collaborative activity plays an important role in the social aspects of self-regulated learning (SRL) development. Peer, teacher and group interactions facilitate support for self-regulation, co-regulation and socially shared regulatory processes. Situated and experiential interplay facilitates personal, co-constructed and…

Development of fast measurements of concentration of NORM U-238 by HPGe

NASA Astrophysics Data System (ADS)

Cha, Seokki; Kim, Siu; Kim, Geehyun

2017-02-01

Naturally Occureed Radioactive Material (NORM) generated from the origin of earth can be found all around us and even people who are not engaged in the work related to radiation have been exposed to unnecessary radiation. This NORM has a potential risk provided that is concentrated or transformed by artificial activities. Likewise, a development of fast measruement method of NORM is emerging to prevent the radiation exposure of the general public and person engaged in the work related to the type of business related thereto who uses the material in which NORM is concentrated or transfromed. Based on such a background, many of countries have tried to manage NORM and carried out regulatory legislation. To effienctly manage NORM, there is need for developing new measurement to quickly and accurately analyze the nuclide and concentration. In this study, development of the fast and reliable measurement was carried out. In addition to confirming the reliability of the fast measurement, we have obtained results that can suggest the possibility of developing another fast measurement. Therefore, as a follow-up, it is possible to develop another fast analytical measurement afterwards. The results of this study will be very useful for the regulatory system to manage NORM. In this study, a review of two indirect measurement methods of NORM U-238 that has used HPGe on the basis of the equilibrium theory of relationships of mother and daughter nuclide at decay-chain of NORM U-238 has been carried out. For comparative study(in order to know reliabily), direct measurement that makes use of alpha spectrometer with complicated pre-processing process was implemented.

Role of transcriptional regulation in the evolution of plant phenotype: A dynamic systems approach.

PubMed

Rodríguez-Mega, Emiliano; Piñeyro-Nelson, Alma; Gutierrez, Crisanto; García-Ponce, Berenice; Sánchez, María De La Paz; Zluhan-Martínez, Estephania; Álvarez-Buylla, Elena R; Garay-Arroyo, Adriana

2015-03-02

A growing body of evidence suggests that alterations in transcriptional regulation of genes involved in modulating development are an important part of phenotypic evolution, and this can be documented among species and within populations. While the effects of differential transcriptional regulation in organismal development have been preferentially studied in animal systems, this phenomenon has also been addressed in plants. In this review, we summarize evidence for cis-regulatory mutations, trans-regulatory changes and epigenetic modifications as molecular events underlying important phenotypic alterations, and thus shaping the evolution of plant development. We postulate that a mechanistic understanding of why such molecular alterations have a key role in development, morphology and evolution will have to rely on dynamic models of complex regulatory networks that consider the concerted action of genetic and nongenetic components, and that also incorporate the restrictions underlying the genotype to phenotype mapping process. Developmental Dynamics, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Integration of new technology into clinical practice after FDA approval.

PubMed

Govil, Ashul; Hao, Steven C

2016-10-01

Development of new medical technology is a crucial part of the advancement of medicine and our ability to better treat patients and their diseases. This process of development is long and arduous and requires a significant investment of human, financial and material capital. However, technology development can be rewarded richly by its impact on patient outcomes and successful sale of the product. One of the major regulatory hurdles to technology development is the Food and Drug Administration (FDA) approval process, which is necessary before a technology can be marketed and sold in the USA. Many businesses, medical providers and consumers believe that the FDA approval process is the only hurdle prior to use of the technology in day-to-day care. In order for the technology to be adopted into clinical use, reimbursement for both the device as well as the associated work performed by physicians and medical staff must be in place. Work and coverage decisions require Current Procedural Terminology (CPT) code development and Relative Value Scale Update Committee (RUC) valuation determination. Understanding these processes is crucial to the timely availability of new technology to patients and providers. Continued and better partnerships between physicians, industry, regulatory bodies and payers will facilitate bringing technology to market sooner and ensure appropriate utilization.

Balancing consumer protection and scientific integrity in the face of uncertainty: the example of gluten-free foods.

PubMed

McCabe, Margaret Sova

2010-01-01

In 2009, gluten-free foods were not only "hot" in the marketplace, several countries, including the United States, continued efforts to define gluten-free and appropriate labeling parameters. The regulatory process illuminates how difficult regulations based on safe scientific thresholds can be for regulators, manufacturers and consumers. This article analyzes the gluten-free regulatory landscape, challenges to defining a safe gluten threshold, and how consumers might need more label information beyond the term "gluten-free." The article includes an overview of international gluten-free regulations, the Food and Drug Administration (FDA) rulemaking process, and issues for consumers.

Health complaints and regulatory reform: Implications for vulnerable populations?

PubMed

Carney, Terry; Beaupert, Fleur; Chiarella, Mary; Bennett, Belinda; Walton, Merrilyn; Kelly, Patrick J; Satchell, Claudette S

2016-03-01

Complaints and disciplinary processes play a significant role in health professional regulation. Many countries are transitioning from models of self-regulation to greater external oversight through systems including meta-regulation, responsive (risk-based) regulation, and "networked governance". Such systems harness, in differing ways, public, private, professional and non-governmental bodies to exert influence over the conduct of health professionals and services. Interesting literature is emerging regarding complainants' motivations and experiences, the impact of complaints processes on health professionals, and identification of features such as complainant and health professional profiles, types of complaints and outcomes. This article concentrates on studies identifying vulnerable groups and their participation in health care regulatory systems.

Identification and role of regulatory non-coding RNAs in Listeria monocytogenes.

PubMed

Izar, Benjamin; Mraheil, Mobarak Abu; Hain, Torsten

2011-01-01

Bacterial regulatory non-coding RNAs control numerous mRNA targets that direct a plethora of biological processes, such as the adaption to environmental changes, growth and virulence. Recently developed high-throughput techniques, such as genomic tiling arrays and RNA-Seq have allowed investigating prokaryotic cis- and trans-acting regulatory RNAs, including sRNAs, asRNAs, untranslated regions (UTR) and riboswitches. As a result, we obtained a more comprehensive view on the complexity and plasticity of the prokaryotic genome biology. Listeria monocytogenes was utilized as a model system for intracellular pathogenic bacteria in several studies, which revealed the presence of about 180 regulatory RNAs in the listerial genome. A regulatory role of non-coding RNAs in survival, virulence and adaptation mechanisms of L. monocytogenes was confirmed in subsequent experiments, thus, providing insight into a multifaceted modulatory function of RNA/mRNA interference. In this review, we discuss the identification of regulatory RNAs by high-throughput techniques and in their functional role in L. monocytogenes.

National Security and Information Technology: The New Regulatory Option?

ERIC Educational Resources Information Center

Irwin, Manley R.

1987-01-01

Summarizes recent developments in information technology research and development, telecommunication services, telephone manufacturing, telecommunication networks, information processing, and U.S. import/export policy. It is concluded that government regulation as a policy strategy depends on how one defines national security. (Author/CLB)

Integrated Regulatory and Metabolic Networks of the Marine Diatom Phaeodactylum tricornutum Predict the Response to Rising CO 2 Levels

DOE PAGES

Levering, Jennifer; Dupont, Christopher L.; Allen, Andrew E.; ...

2017-02-14

Diatoms are eukaryotic microalgae that are responsible for up to 40% of the ocean’s primary productivity. How diatoms respond to environmental perturbations such as elevated carbon concentrations in the atmosphere is currently poorly understood. We developed a transcriptional regulatory network based on various transcriptome sequencing expression libraries for different environmental responses to gain insight into the marine diatom’s metabolic and regulatory interactions and provide a comprehensive framework of responses to increasing atmospheric carbon levels. This transcriptional regulatory network was integrated with a recently published genome-scale metabolic model of Phaeodactylum tricornutum to explore the connectivity of the regulatory network and sharedmore » metabolites. The integrated regulatory and metabolic model revealed highly connected modules within carbon and nitrogen metabolism. P. tricornutum’s response to rising carbon levels was analyzed by using the recent genome-scale metabolic model with cross comparison to experimental manipulations of carbon dioxide. Using a systems biology approach, we studied the response of the marine diatom Phaeodactylum tricornutum to changing atmospheric carbon concentrations on an ocean-wide scale. By integrating an available genome-scale metabolic model and a newly developed transcriptional regulatory network inferred from transcriptome sequencing expression data, we demonstrate that carbon metabolism and nitrogen metabolism are strongly connected and the genes involved are coregulated in this model diatom. These tight regulatory constraints could play a major role during the adaptation of P. tricornutum to increasing carbon levels. The transcriptional regulatory network developed can be further used to study the effects of different environmental perturbations on P. tricornutum’s metabolism.« less

Integrated Regulatory and Metabolic Networks of the Marine Diatom Phaeodactylum tricornutum Predict the Response to Rising CO 2 Levels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Levering, Jennifer; Dupont, Christopher L.; Allen, Andrew E.

Diatoms are eukaryotic microalgae that are responsible for up to 40% of the ocean’s primary productivity. How diatoms respond to environmental perturbations such as elevated carbon concentrations in the atmosphere is currently poorly understood. We developed a transcriptional regulatory network based on various transcriptome sequencing expression libraries for different environmental responses to gain insight into the marine diatom’s metabolic and regulatory interactions and provide a comprehensive framework of responses to increasing atmospheric carbon levels. This transcriptional regulatory network was integrated with a recently published genome-scale metabolic model of Phaeodactylum tricornutum to explore the connectivity of the regulatory network and sharedmore » metabolites. The integrated regulatory and metabolic model revealed highly connected modules within carbon and nitrogen metabolism. P. tricornutum’s response to rising carbon levels was analyzed by using the recent genome-scale metabolic model with cross comparison to experimental manipulations of carbon dioxide. Using a systems biology approach, we studied the response of the marine diatom Phaeodactylum tricornutum to changing atmospheric carbon concentrations on an ocean-wide scale. By integrating an available genome-scale metabolic model and a newly developed transcriptional regulatory network inferred from transcriptome sequencing expression data, we demonstrate that carbon metabolism and nitrogen metabolism are strongly connected and the genes involved are coregulated in this model diatom. These tight regulatory constraints could play a major role during the adaptation of P. tricornutum to increasing carbon levels. The transcriptional regulatory network developed can be further used to study the effects of different environmental perturbations on P. tricornutum’s metabolism.« less

GRN2SBML: automated encoding and annotation of inferred gene regulatory networks complying with SBML.

PubMed

Vlaic, Sebastian; Hoffmann, Bianca; Kupfer, Peter; Weber, Michael; Dräger, Andreas

2013-09-01

GRN2SBML automatically encodes gene regulatory networks derived from several inference tools in systems biology markup language. Providing a graphical user interface, the networks can be annotated via the simple object access protocol (SOAP)-based application programming interface of BioMart Central Portal and minimum information required in the annotation of models registry. Additionally, we provide an R-package, which processes the output of supported inference algorithms and automatically passes all required parameters to GRN2SBML. Therefore, GRN2SBML closes a gap in the processing pipeline between the inference of gene regulatory networks and their subsequent analysis, visualization and storage. GRN2SBML is freely available under the GNU Public License version 3 and can be downloaded from http://www.hki-jena.de/index.php/0/2/490. General information on GRN2SBML, examples and tutorials are available at the tool's web page.

Genome-wide network of regulatory genes for construction of a chordate embryo.

PubMed

Shoguchi, Eiichi; Hamaguchi, Makoto; Satoh, Nori

2008-04-15

Animal development is controlled by gene regulation networks that are composed of sequence-specific transcription factors (TF) and cell signaling molecules (ST). Although housekeeping genes have been reported to show clustering in the animal genomes, whether the genes comprising a given regulatory network are physically clustered on a chromosome is uncertain. We examined this question in the present study. Ascidians are the closest living relatives of vertebrates, and their tadpole-type larva represents the basic body plan of chordates. The Ciona intestinalis genome contains 390 core TF genes and 119 major ST genes. Previous gene disruption assays led to the formulation of a basic chordate embryonic blueprint, based on over 3000 genetic interactions among 79 zygotic regulatory genes. Here, we mapped the regulatory genes, including all 79 regulatory genes, on the 14 pairs of Ciona chromosomes by fluorescent in situ hybridization (FISH). Chromosomal localization of upstream and downstream regulatory genes demonstrates that the components of coherent developmental gene networks are evenly distributed over the 14 chromosomes. Thus, this study provides the first comprehensive evidence that the physical clustering of regulatory genes, or their target genes, is not relevant for the genome-wide control of gene expression during development.

Functional analysis of regulatory single-nucleotide polymorphisms.

PubMed

Pampín, Sandra; Rodríguez-Rey, José C

2007-04-01

The identification of regulatory polymorphisms has become a key problem in human genetics. In the past few years there has been a conceptual change in the way in which regulatory single-nucleotide polymorphisms are studied. We revise the new approaches and discuss how gene expression studies can contribute to a better knowledge of the genetics of common diseases. New techniques for the association of single-nucleotide polymorphisms with changes in gene expression have been recently developed. This, together with a more comprehensive use of the old in-vitro methods, has produced a great amount of genetic information. When added to current databases, it will help to design better tools for the detection of regulatory single-nucleotide polymorphisms. The identification of functional regulatory single-nucleotide polymorphisms cannot be done by the simple inspection of DNA sequence. In-vivo techniques, based on primer-extension, and the more recently developed 'haploChIP' allow the association of gene variants to changes in gene expression. Gene expression analysis by conventional in-vitro techniques is the only way to identify the functional consequences of regulatory single-nucleotide polymorphisms. The amount of information produced in the last few years will help to refine the tools for the future analysis of regulatory gene variants.

Meeting the challenges of medical countermeasure development.

PubMed

Maher, Carmen; Hu-Primmer, Jean; MacGill, Tracy; Courtney, Brooke; Borio, Luciana

2012-09-01

Despite substantial investments since the events of 2001, much work remains to prepare the nation for a chemical, biological, radiological or nuclear (CBRN) attack or to respond to an emerging infectious disease threat. Following a 2010 review of the US Public Health Emergency Medical Countermeasures Enterprise, FDA launched its Medical Countermeasures initiative (MCMi) to facilitate the development and availability of medical products to counter CBRN and emerging disease threats. As a regulatory agency, FDA has a unique and critical part to play in this national undertaking. Using a three-pillar approach, FDA is addressing key challenges associated with the regulatory review process for medical countermeasures; gaps in regulatory science for MCM development and evaluation; and issues related to the legal, regulatory and policy framework for an effective public health response. Filling the gaps in the MCM Enterprise is a huge national undertaking, requiring the collaboration of all stakeholders, including federal partners, current and prospective developers of medical countermeasures, relevant research organizations, and state and local responders. Especially critical to success are an appreciation of the long timelines, risks and high costs associated with developing medical countermeasures - and the systems to deliver them - and the requisite support of all stakeholders, including national leadership. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

FK506 biosynthesis is regulated by two positive regulatory elements in Streptomyces tsukubaensis

PubMed Central

2012-01-01

Background FK506 (Tacrolimus) is an important immunosuppressant, produced by industrial biosynthetic processes using various Streptomyces species. Considering the complex structure of FK506, it is reasonable to expect complex regulatory networks controlling its biosynthesis. Regulatory elements, present in gene clusters can have a profound influence on the final yield of target product and can play an important role in development of industrial bioprocesses. Results Three putative regulatory elements, namely fkbR, belonging to the LysR-type family, fkbN, a large ATP-binding regulator of the LuxR family (LAL-type) and allN, a homologue of AsnC family regulatory proteins, were identified in the FK506 gene cluster from Streptomyces tsukubaensis NRRL 18488, a progenitor of industrial strains used for production of FK506. Inactivation of fkbN caused a complete disruption of FK506 biosynthesis, while inactivation of fkbR resulted in about 80% reduction of FK506 yield. No functional role in the regulation of the FK506 gene cluster has been observed for the allN gene. Using RT-PCR and a reporter system based on a chalcone synthase rppA, we demonstrated, that in the wild type as well as in fkbN- and fkbR-inactivated strains, fkbR is transcribed in all stages of cultivation, even before the onset of FK506 production, whereas fkbN expression is initiated approximately with the initiation of FK506 production. Surprisingly, inactivation of fkbN (or fkbR) does not abolish the transcription of the genes in the FK506 gene cluster in general, but may reduce expression of some of the tested biosynthetic genes. Finally, introduction of a second copy of the fkbR or fkbN genes under the control of the strong ermE* promoter into the wild type strain resulted in 30% and 55% of yield improvement, respectively. Conclusions Our results clearly demonstrate the positive regulatory role of fkbR and fkbN genes in FK506 biosynthesis in S. tsukubaensis NRRL 18488. We have shown that regulatory mechanisms can differ substantially from other, even apparently closely similar FK506-producing strains, reported in literature. Finally, we have demonstrated the potential of these genetically modified strains of S. tsukubaensis for improving the yield of fermentative processes for production of FK506. PMID:23083511

Finding Groups Using Model-Based Cluster Analysis: Heterogeneous Emotional Self-Regulatory Processes and Heavy Alcohol Use Risk

ERIC Educational Resources Information Center

Mun, Eun Young; von Eye, Alexander; Bates, Marsha E.; Vaschillo, Evgeny G.

2008-01-01

Model-based cluster analysis is a new clustering procedure to investigate population heterogeneity utilizing finite mixture multivariate normal densities. It is an inferentially based, statistically principled procedure that allows comparison of nonnested models using the Bayesian information criterion to compare multiple models and identify the…

Exploring the Relationship between Self-Regulated Vocabulary Learning and Web-Based Collaboration

ERIC Educational Resources Information Center

Liu, Sarah Hsueh-Jui; Lan, Yu-Ju; Ho, Cloudia Ya-Yu

2014-01-01

Collaborative learning has placed an emphasis on co-constructing knowledge by sharing and negotiating meaning for problem-solving activities, and this cannot be accomplished without governing the self-regulatory processes of students. This study employed a Web-based tool, Google Docs, to determine the effects of Web-based collaboration on…

Benefits of Traditional Hydro to MHK and the Regulatory Process

DOE Office of Scientific and Technical Information (OSTI.GOV)

Levine, Aaron

Presentation discussing how traditional hydropower laws and regulations can be leveraged when developing marine and hydrokinetic projects as well as exceptions to FERC licensing for hydrokinetic projects.

Integrated Process Modeling-A Process Validation Life Cycle Companion.

PubMed

Zahel, Thomas; Hauer, Stefan; Mueller, Eric M; Murphy, Patrick; Abad, Sandra; Vasilieva, Elena; Maurer, Daniel; Brocard, Cécile; Reinisch, Daniela; Sagmeister, Patrick; Herwig, Christoph

2017-10-17

During the regulatory requested process validation of pharmaceutical manufacturing processes, companies aim to identify, control, and continuously monitor process variation and its impact on critical quality attributes (CQAs) of the final product. It is difficult to directly connect the impact of single process parameters (PPs) to final product CQAs, especially in biopharmaceutical process development and production, where multiple unit operations are stacked together and interact with each other. Therefore, we want to present the application of Monte Carlo (MC) simulation using an integrated process model (IPM) that enables estimation of process capability even in early stages of process validation. Once the IPM is established, its capability in risk and criticality assessment is furthermore demonstrated. IPMs can be used to enable holistic production control strategies that take interactions of process parameters of multiple unit operations into account. Moreover, IPMs can be trained with development data, refined with qualification runs, and maintained with routine manufacturing data which underlines the lifecycle concept. These applications will be shown by means of a process characterization study recently conducted at a world-leading contract manufacturing organization (CMO). The new IPM methodology therefore allows anticipation of out of specification (OOS) events, identify critical process parameters, and take risk-based decisions on counteractions that increase process robustness and decrease the likelihood of OOS events.

An Integrative Approach to Computational Modelling of the Gene Regulatory Network Controlling Clostridium botulinum Type A1 Toxin Production.

PubMed

Ihekwaba, Adaoha E C; Mura, Ivan; Walshaw, John; Peck, Michael W; Barker, Gary C

2016-11-01

Clostridium botulinum produces botulinum neurotoxins (BoNTs), highly potent substances responsible for botulism. Currently, mathematical models of C. botulinum growth and toxigenesis are largely aimed at risk assessment and do not include explicit genetic information beyond group level but integrate many component processes, such as signalling, membrane permeability and metabolic activity. In this paper we present a scheme for modelling neurotoxin production in C. botulinum Group I type A1, based on the integration of diverse information coming from experimental results available in the literature. Experiments show that production of BoNTs depends on the growth-phase and is under the control of positive and negative regulatory elements at the intracellular level. Toxins are released as large protein complexes and are associated with non-toxic components. Here, we systematically review and integrate those regulatory elements previously described in the literature for C. botulinum Group I type A1 into a population dynamics model, to build the very first computational model of toxin production at the molecular level. We conduct a validation of our model against several items of published experimental data for different wild type and mutant strains of C. botulinum Group I type A1. The result of this process underscores the potential of mathematical modelling at the cellular level, as a means of creating opportunities in developing new strategies that could be used to prevent botulism; and potentially contribute to improved methods for the production of toxin that is used for therapeutics.